3037 – TWO DISTINCT ISOFORMS OF MLLT3 REGULATE HUMAN HSC FUNCTION
MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacter...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Vavilina, Anastasia [verfasserIn] |
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| Format: |
E-Artikel |
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| Erschienen: |
2021transfer abstract |
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| Übergeordnetes Werk: |
Enthalten in: Interfacing 2D M - Rawat, Ashima ELSEVIER, 2021, official publication of the International Society for Experimental Hematology, Amsterdam [u.a] |
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| Übergeordnetes Werk: |
volume:100 ; year:2021 ; pages:60 |
| Links: |
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| DOI / URN: |
10.1016/j.exphem.2021.12.257 |
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ELV05764425X |
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| 520 | |a MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. | ||
| 520 | |a MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. | ||
| 700 | 1 | |a Calvanese, Vincenzo |4 oth | |
| 700 | 1 | |a Fares, Iman |4 oth | |
| 700 | 1 | |a Garcia, Sandra Capellera |4 oth | |
| 700 | 1 | |a Jami-Alahmadi, Yasaman |4 oth | |
| 700 | 1 | |a Wang, Yanling |4 oth | |
| 700 | 1 | |a Goodridge, Helen |4 oth | |
| 700 | 1 | |a Shin, Juliana |4 oth | |
| 700 | 1 | |a Wohlschlegel, James |4 oth | |
| 700 | 1 | |a Mikkola, Hanna |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |n Elsevier Science |a Rawat, Ashima ELSEVIER |t Interfacing 2D M |d 2021 |d official publication of the International Society for Experimental Hematology |g Amsterdam [u.a] |w (DE-627)ELV006315852 |
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| 936 | b | k | |a 35.18 |j Kolloidchemie |j Grenzflächenchemie |q VZ |
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2021transfer abstract |
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33.68 35.18 52.78 |
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2021 |
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10.1016/j.exphem.2021.12.257 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001767.pica (DE-627)ELV05764425X (ELSEVIER)S0301-472X(21)00716-5 DE-627 ger DE-627 rakwb 670 530 660 VZ 33.68 bkl 35.18 bkl 52.78 bkl Vavilina, Anastasia verfasserin aut 3037 – TWO DISTINCT ISOFORMS OF MLLT3 REGULATE HUMAN HSC FUNCTION 2021transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. Calvanese, Vincenzo oth Fares, Iman oth Garcia, Sandra Capellera oth Jami-Alahmadi, Yasaman oth Wang, Yanling oth Goodridge, Helen oth Shin, Juliana oth Wohlschlegel, James oth Mikkola, Hanna oth Enthalten in Elsevier Science Rawat, Ashima ELSEVIER Interfacing 2D M 2021 official publication of the International Society for Experimental Hematology Amsterdam [u.a] (DE-627)ELV006315852 volume:100 year:2021 pages:60 https://doi.org/10.1016/j.exphem.2021.12.257 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA 33.68 Oberflächen Dünne Schichten Grenzflächen Physik VZ 35.18 Kolloidchemie Grenzflächenchemie VZ 52.78 Oberflächentechnik Wärmebehandlung VZ AR 100 2021 60 100.2021, S60- |
| spelling |
10.1016/j.exphem.2021.12.257 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001767.pica (DE-627)ELV05764425X (ELSEVIER)S0301-472X(21)00716-5 DE-627 ger DE-627 rakwb 670 530 660 VZ 33.68 bkl 35.18 bkl 52.78 bkl Vavilina, Anastasia verfasserin aut 3037 – TWO DISTINCT ISOFORMS OF MLLT3 REGULATE HUMAN HSC FUNCTION 2021transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. Calvanese, Vincenzo oth Fares, Iman oth Garcia, Sandra Capellera oth Jami-Alahmadi, Yasaman oth Wang, Yanling oth Goodridge, Helen oth Shin, Juliana oth Wohlschlegel, James oth Mikkola, Hanna oth Enthalten in Elsevier Science Rawat, Ashima ELSEVIER Interfacing 2D M 2021 official publication of the International Society for Experimental Hematology Amsterdam [u.a] (DE-627)ELV006315852 volume:100 year:2021 pages:60 https://doi.org/10.1016/j.exphem.2021.12.257 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA 33.68 Oberflächen Dünne Schichten Grenzflächen Physik VZ 35.18 Kolloidchemie Grenzflächenchemie VZ 52.78 Oberflächentechnik Wärmebehandlung VZ AR 100 2021 60 100.2021, S60- |
| allfields_unstemmed |
10.1016/j.exphem.2021.12.257 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001767.pica (DE-627)ELV05764425X (ELSEVIER)S0301-472X(21)00716-5 DE-627 ger DE-627 rakwb 670 530 660 VZ 33.68 bkl 35.18 bkl 52.78 bkl Vavilina, Anastasia verfasserin aut 3037 – TWO DISTINCT ISOFORMS OF MLLT3 REGULATE HUMAN HSC FUNCTION 2021transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. Calvanese, Vincenzo oth Fares, Iman oth Garcia, Sandra Capellera oth Jami-Alahmadi, Yasaman oth Wang, Yanling oth Goodridge, Helen oth Shin, Juliana oth Wohlschlegel, James oth Mikkola, Hanna oth Enthalten in Elsevier Science Rawat, Ashima ELSEVIER Interfacing 2D M 2021 official publication of the International Society for Experimental Hematology Amsterdam [u.a] (DE-627)ELV006315852 volume:100 year:2021 pages:60 https://doi.org/10.1016/j.exphem.2021.12.257 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA 33.68 Oberflächen Dünne Schichten Grenzflächen Physik VZ 35.18 Kolloidchemie Grenzflächenchemie VZ 52.78 Oberflächentechnik Wärmebehandlung VZ AR 100 2021 60 100.2021, S60- |
| allfieldsGer |
10.1016/j.exphem.2021.12.257 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001767.pica (DE-627)ELV05764425X (ELSEVIER)S0301-472X(21)00716-5 DE-627 ger DE-627 rakwb 670 530 660 VZ 33.68 bkl 35.18 bkl 52.78 bkl Vavilina, Anastasia verfasserin aut 3037 – TWO DISTINCT ISOFORMS OF MLLT3 REGULATE HUMAN HSC FUNCTION 2021transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. Calvanese, Vincenzo oth Fares, Iman oth Garcia, Sandra Capellera oth Jami-Alahmadi, Yasaman oth Wang, Yanling oth Goodridge, Helen oth Shin, Juliana oth Wohlschlegel, James oth Mikkola, Hanna oth Enthalten in Elsevier Science Rawat, Ashima ELSEVIER Interfacing 2D M 2021 official publication of the International Society for Experimental Hematology Amsterdam [u.a] (DE-627)ELV006315852 volume:100 year:2021 pages:60 https://doi.org/10.1016/j.exphem.2021.12.257 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA 33.68 Oberflächen Dünne Schichten Grenzflächen Physik VZ 35.18 Kolloidchemie Grenzflächenchemie VZ 52.78 Oberflächentechnik Wärmebehandlung VZ AR 100 2021 60 100.2021, S60- |
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MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. |
| abstractGer |
MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. |
| abstract_unstemmed |
MLLT3 was recently identified as a critical regulator of human hematopoietic stem cell (HSC) expansion. Analysis of RNA-seq data and epigenetic marks associated with MLLT3 gene in human HSCs revealed that in addition to the full-length MLLT3 (here called MLLT3-L), HSCs express a hitherto-uncharacterized isoform, named MLLT3-S. This isoform is transcribed from its own TSS and predicted to encode a truncated protein retaining the AHD domain enabling protein-protein interactions, but lacking the chromatin-binding YEATS domain. We verified expression of MLLT3-S transcript in human HSCs using RNA-seq, q-RT-PCR and 5’RACE, and confirmed the presence of truncated protein in human cell lines overexpressing V5-tagged MLLT3-S. IP-MS suggested MLLT3-S binds MLLT3-L protein partners in the superelongation and DOT1L complexes. As predicted from the functional domains, MLLT3-S was unable to bind chromatin, suggesting it may function indirectly by sequestering MLLT3-L partners. Although both isoforms are highly enriched in human HSCs, MLLT3-L is already expressed in hemogenic endothelium(HE), whereas MLLT3-S expression is induced only after HSC emerge from HE and mature into functional HSC. RNA-seq analysis of human fetal liver HSPCs overexpressing MLLT3-S or MLLT3-L suggests MLLT3-S may control HSC dynamics by having opposite effects on HSC expansion and metabolic activity than MLLT3-L. Knockdown of MLLT3-S in cultured cord blood HSCs resulted in immediate relative expansion of the most undifferentiated HSPC population, whereas knockdown of MLLT3-L triggered their premature differentiation. While overexpression of MLLT3-L in cord blood HSCs promoted their expansion, overexpression of MLLT3-S did not. Our data suggests that the balance of MLLT3-L and MLLT3-S expression is involved in regulating HSC expansion and maintenance modes, and critical for sustaining lifelong hematopoiesis. |
| collection_details |
GBV_USEFLAG_U GBV_ELV SYSFLAG_U SSG-OLC-PHA |
| title_short |
3037 – TWO DISTINCT ISOFORMS OF MLLT3 REGULATE HUMAN HSC FUNCTION |
| url |
https://doi.org/10.1016/j.exphem.2021.12.257 |
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| author2 |
Calvanese, Vincenzo Fares, Iman Garcia, Sandra Capellera Jami-Alahmadi, Yasaman Wang, Yanling Goodridge, Helen Shin, Juliana Wohlschlegel, James Mikkola, Hanna |
| author2Str |
Calvanese, Vincenzo Fares, Iman Garcia, Sandra Capellera Jami-Alahmadi, Yasaman Wang, Yanling Goodridge, Helen Shin, Juliana Wohlschlegel, James Mikkola, Hanna |
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| doi_str |
10.1016/j.exphem.2021.12.257 |
| up_date |
2024-07-06T16:44:36.606Z |
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