MyoD1 localization at the nuclear periphery is mediated by association of WFS1 with active enhancers
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PROVIDER: PRJNA1065846 | ENA |
REPOSITORIES: ENA
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Project description:Spatial organization of the mammalian genome influences gene expression and cell identity. While association of genes with the nuclear periphery is commonly linked to transcriptional repression, also active, expressed genes can localize at the nuclear periphery. The transcriptionally active MyoD1 gene, a master regulator of myogenesis, exhibits peripheral localization in proliferating myoblasts, yet the underlying mechanisms remain elusive. Using a newly generated reporter cell line, we demonstrate here that peripheral association of the MyoD1 locus is independent of mechanisms involved in heterochromatin anchoring. We identify a set of nuclear envelope transmembrane proteins, particularly WFS1, that actively tether MyoD1 to the nuclear periphery. WFS1 primarily associates with active distal enhancer elements upstream of MyoD1, and with a subset of enhancers enriched in active histone marks genome-wide, which are linked to expressed myogenic genes. Overall, our data identify a novel mechanism involved in tethering active genes to the nuclear periphery. This research was funded in whole or in part by the Austrian Science Fund (FWF) [P29713-B28, P32512-B and P36503-B] to Roland Foisner and a doctorate program funded by the Austrian Science Fund (FWF) [W1261-B28].
2025-01-20 | GSE253460 | GEO
Project description:Basic helix-loop-helix (bHLH) pioneer transcription factors Myod1 and Ascl1 are biochemically related but produce fundamentally different outcomes when expressed in fibroblasts: Myod1 produces muscle cells and Ascl1 induces neurons. Here, we sought to investigate the molecular mechanisms explaining the differential activity. Surprisingly, we found a large overlap in the overall binding patterns of Ascl1 and Myod1 in fibroblasts, with both transcription factors accessing both neuronal and myogenic targets. We also observed similar changes in chromatin accessibility and transcriptional activation. Yet, Myod1 predominantly induced a muscle program and Ascl1 a neuronal program. We found that differences in binding affinity at key targets resulted in largely distinct reprogramming outcomes. Accordingly, exchanging Myod1’s C-terminal protein-protein interacting domain and DNA-binding basic domain with those of Ascl1 induces an Ascl1-like binding and converts Myod1 into a pro-neuronal factor. Finally, we found that co-expression of Myod1 with the transcriptional repressor Myt1l inhibits induction of the muscle program and yields functional neuronal cells. Our findings are compatible with the notion that pioneer factor activity is associated with high-affinity protein-DNA and suggest that promiscuous binding of pioneer factors can induce unspecific lineage features which need to be kept in check by co-factor interactions.
2020-02-03 | GSE126413 | GEO
Project description:Basic helix-loop-helix (bHLH) pioneer transcription factors Myod1 and Ascl1 are biochemically related but produce fundamentally different outcomes when expressed in fibroblasts: Myod1 produces muscle cells and Ascl1 induces neurons. Here, we sought to investigate the molecular mechanisms explaining the differential activity. Surprisingly, we found a large overlap in the overall binding patterns of Ascl1 and Myod1 in fibroblasts, with both transcription factors accessing both neuronal and myogenic targets. We also observed similar changes in chromatin accessibility and transcriptional activation. Yet, Myod1 predominantly induced a muscle program and Ascl1 a neuronal program. We found that differences in binding affinity at key targets resulted in largely distinct reprogramming outcomes. Accordingly, exchanging Myod1’s C-terminal protein-protein interacting domain and DNA-binding basic domain with those of Ascl1 induces an Ascl1-like binding and converts Myod1 into a pro-neuronal factor. Finally, we found that co-expression of Myod1 with the transcriptional repressor Myt1l inhibits induction of the muscle program and yields functional neuronal cells. Our findings are compatible with the notion that pioneer factor activity is associated with high-affinity protein-DNA and suggest that promiscuous binding of pioneer factors can induce unspecific lineage features which need to be kept in check by co-factor interactions.
2020-02-03 | GSE126412 | GEO
Project description:Skeletal muscle is a dynamic tissue the size of which can be remodeled through the concerted actions of various cues. Here, we investigated the skeletal muscle transcriptional program and identified key tissue-specific regulatory genetic elements. Our results show that Myod1 is bound to numerous skeletal muscle enhancers in collaboration with the glucocorticoid receptor (GR) to control gene expression. Remarkably, transcriptional activation controlled by these factors occurs through direct contacts with the promoter region of target genes, via the CpG-bound transcription factor Nrf1, and the formation of Ctcf-anchored chromatin loops, in a myofiber-specific manner. Moreover, we demonstrate that GR negatively controls muscle mass and strength in mice by down-regulating anabolic pathways. Taken together, our data establish Myod1, GR and Nrf1 as key players of muscle-specific enhancer-promoter communication that orchestrate myofiber size regulation.
| S-EPMC8096230 | biostudies-literature
Project description:Basic helix-loop-helix (bHLH) pioneer transcription factors Myod1 and Ascl1 are biochemically related but produce fundamentally different outcomes when expressed in fibroblasts: Myod1 produces muscle cells and Ascl1 induces neurons. Here, we sought to investigate the molecular mechanisms explaining the differential activity. Surprisingly, we found a large overlap in the overall binding patterns of Ascl1 and Myod1 in fibroblasts, with both transcription factors accessing both neuronal and myogenic targets. We also observed similar changes in chromatin accessibility and transcriptional activation. Yet, Myod1 predominantly induced a muscle program and Ascl1 a neuronal program. We found that differences in binding affinity at key targets resulted in largely distinct reprogramming outcomes. Accordingly, exchanging Myod1’s C-terminal protein-protein interacting domain and DNA-binding basic domain with those of Ascl1 induces an Ascl1-like binding and converts Myod1 into a pro-neuronal factor. Finally, we found that co-expression of Myod1 with the transcriptional repressor Myt1l inhibits induction of the muscle program and yields functional neuronal cells. Our findings are compatible with the notion that pioneer factor activity is associated with high-affinity protein-DNA and suggest that promiscuous binding of pioneer factors can induce unspecific lineage features which need to be kept in check by co-factor interactions.
2020-02-03 | GSE126411 | GEO
Project description:Basic helix-loop-helix (bHLH) pioneer transcription factors Myod1 and Ascl1 are biochemically related but produce fundamentally different outcomes when expressed in fibroblasts: Myod1 produces muscle cells and Ascl1 induces neurons. Here, we sought to investigate the molecular mechanisms explaining the differential activity. Surprisingly, we found a large overlap in the overall binding patterns of Ascl1 and Myod1 in fibroblasts, with both transcription factors accessing both neuronal and myogenic targets. We also observed similar changes in chromatin accessibility and transcriptional activation. Yet, Myod1 predominantly induced a muscle program and Ascl1 a neuronal program. We found that differences in binding affinity at key targets resulted in largely distinct reprogramming outcomes. Accordingly, exchanging Myod1’s C-terminal protein-protein interacting domain and DNA-binding basic domain with those of Ascl1 induces an Ascl1-like binding and converts Myod1 into a pro-neuronal factor. Finally, we found that co-expression of Myod1 with the transcriptional repressor Myt1l inhibits induction of the muscle program and yields functional neuronal cells. Our findings are compatible with the notion that pioneer factor activity is associated with high-affinity protein-DNA and suggest that promiscuous binding of pioneer factors can induce unspecific lineage features which need to be kept in check by co-factor interactions.
2020-02-03 | GSE126410 | GEO
Project description:Basic helix-loop-helix (bHLH) pioneer transcription factors Myod1 and Ascl1 are biochemically related but produce fundamentally different outcomes when expressed in fibroblasts: Myod1 produces muscle cells and Ascl1 induces neurons. Here, we sought to investigate the molecular mechanisms explaining the differential activity. Surprisingly, we found a large overlap in the overall binding patterns of Ascl1 and Myod1 in fibroblasts, with both transcription factors accessing both neuronal and myogenic targets. We also observed similar changes in chromatin accessibility and transcriptional activation. Yet, Myod1 predominantly induced a muscle program and Ascl1 a neuronal program. We found that differences in binding affinity at key targets resulted in largely distinct reprogramming outcomes. Accordingly, exchanging Myod1’s C-terminal protein-protein interacting domain and DNA-binding basic domain with those of Ascl1 induces an Ascl1-like binding and converts Myod1 into a pro-neuronal factor. Finally, we found that co-expression of Myod1 with the transcriptional repressor Myt1l inhibits induction of the muscle program and yields functional neuronal cells. Our findings are compatible with the notion that pioneer factor activity is associated with high-affinity protein-DNA and suggest that promiscuous binding of pioneer factors can induce unspecific lineage features which need to be kept in check by co-factor interactions.
2020-02-03 | GSE140381 | GEO
Project description:Circular chromatin confirmation capture in rhabdomyosarcoma cells was performed with viewpoints at the PAX3-FOXO1 bound super enhancer upstream of MYOD1, and also at the MYOD1 promoter, to find support for looping between these two genetic elements almost 80 thousand base pairs apart.
2017-04-27 | GSE83727 | GEO
Project description:The conversion of fibroblasts to myotubes by forced expression of MyoD1 is among the earliest demonstrations of reprogramming of vertebrate cell state. To gain insights into the chromatin state of genes required for reprogramming, we profiled H3K4me3, H3K27me3 and H3K9me3. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. ChIP was performed using an antibody against H3K4me3, H3K27me3 and H3K9me3.
2010-07-24 | E-GEOD-23078 | biostudies-arrayexpress
Project description:In the present study we show that the master myogenic regulatory factor, MYOD1, is a positive modulator of molecular clock amplitude and functions with the core clock factors for expression of clock-controlled genes in skeletal muscle. We demonstrate that MYOD1 directly regulates the expression and circadian amplitude of the positive core clock factor Bmal1. We identify a non-canonical E-box element in Bmal1 and demonstrate that is required for full MYOD1-responsiveness. Bimolecular fluorescence complementation assays demonstrate that MYOD1 colocalizes with both BMAL1 and CLOCK throughout myonuclei. We demonstrate that MYOD1 and BMAL1:CLOCK work in a synergistic fashion through a tandem Ebox to regulate the expression and amplitude of the muscle specific clock-controlled gene, Titin-cap (Tcap). In conclusion, these findings reveal mechanistic roles for the muscle specific transcription factor MYOD1 in the regulation of amplitude of the molecular clock as well as synergistic regulation of clock-controlled genes in skeletal muscle.
2018-11-02 | GSE122082 | GEO