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Dual functions of TAF7L in adipocyte differentiation.

Zhou H, Kaplan T, Li Y, Grubisic I, Zhang Z, Wang PJ, Eisen MB, Tjian R - Elife (2013)

Bottom Line: Depletion of TAF7L reduced adipocyte-specific gene expression, compromised adipocyte differentiation, and WAT development as well.Genome-wide mRNA-seq expression profiling and ChIP-seq binding studies confirmed that TAF7L is required for activating adipocyte-specific genes via a dual mechanism wherein it interacts with PPARγ at enhancers and TBP/Pol II at core promoters.In vitro binding studies confirmed that TAF7L forms complexes with both TBP and PPARγ.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology , Howard Hughes Medical Institute, University of California, Berkeley , Berkeley , United States ; Li Ka Shing Center For Biomedical and Health Sciences, CIRM Center of Excellence, University of California, Berkeley , Berkeley , United States.

ABSTRACT
The diverse transcriptional mechanisms governing cellular differentiation and development of mammalian tissue remains poorly understood. Here we report that TAF7L, a paralogue of TFIID subunit TAF7, is enriched in adipocytes and white fat tissue (WAT) in mouse. Depletion of TAF7L reduced adipocyte-specific gene expression, compromised adipocyte differentiation, and WAT development as well. Ectopic expression of TAF7L in myoblasts reprograms these muscle precursors into adipocytes upon induction. Genome-wide mRNA-seq expression profiling and ChIP-seq binding studies confirmed that TAF7L is required for activating adipocyte-specific genes via a dual mechanism wherein it interacts with PPARγ at enhancers and TBP/Pol II at core promoters. In vitro binding studies confirmed that TAF7L forms complexes with both TBP and PPARγ. These findings suggest that TAF7L plays an integral role in adipocyte gene expression by targeting enhancers as a cofactor for PPARγ and promoters as a component of the core transcriptional machinery.DOI:http://dx.doi.org/10.7554/eLife.00170.001.

No MeSH data available.


Related in: MedlinePlus

Dual functions of TAF7L in adipocyte differentiation.TAF7L expression is enriched during C3H10T1/2 MSCs adipocyte differentiation while other TFIID subunits (TAFs) decrease in expression. TAF7L regulates adipogenesis by associating with TBP as a component of adipocyte TFIID complex at promoters and with PPARγ or other adipocyte transcriptional factors (ATFs) as a cofactor at enhancers on adipocyte-specific genes, providing the mechanisms of its dual roles during differentiation. General highly-expressed genes are those with high expression before and after adipocyte differentiation include a portion of housekeeping genes; adipocyte-specific genes are those required for adipocyte differentiation and highly upregulated during adipocyte differentiation. TAFs,TBP-associated factors; ATFs, adipocyte transcriptional factors; BEs, binding elements.DOI:http://dx.doi.org/10.7554/eLife.00170.014
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fig8: Dual functions of TAF7L in adipocyte differentiation.TAF7L expression is enriched during C3H10T1/2 MSCs adipocyte differentiation while other TFIID subunits (TAFs) decrease in expression. TAF7L regulates adipogenesis by associating with TBP as a component of adipocyte TFIID complex at promoters and with PPARγ or other adipocyte transcriptional factors (ATFs) as a cofactor at enhancers on adipocyte-specific genes, providing the mechanisms of its dual roles during differentiation. General highly-expressed genes are those with high expression before and after adipocyte differentiation include a portion of housekeeping genes; adipocyte-specific genes are those required for adipocyte differentiation and highly upregulated during adipocyte differentiation. TAFs,TBP-associated factors; ATFs, adipocyte transcriptional factors; BEs, binding elements.DOI:http://dx.doi.org/10.7554/eLife.00170.014

Mentions: It is well-documented that the adult human body contains cells residing in the adipose tissue, referred to as Adipose-derived Stem Cells (ASCs) (DeLany et al., 2005; Feve, 2005; Gonzalez, 2005; Gerlach et al., 2012). ASCs resemble mesenchymal stem cells (MSCs) in terms of their ability to differentiate into multiple lineages including adipocytes, myotubes, osteocytes, and cartilage under appropriate developmental cues (Gornostaeva et al., 2006). Given that increased numbers of adipocytes, a major underlying cause of obesity, are primarily derived from MSCs and/or ASCs (Bowers and Lane, 2008), we chose C3H10T1/2 MSCs as our cell culture model system for studying adipogenesis in large measure because MSCs efficiently recapitulate aspects of adipocyte differentiation and in vivo fat development. Using this MSC culture model as well as Taf7l KO mouse model for our in vitro and in vivo studies, we unexpectedly identified Taf7l as a key regulator of adipogenesis; adding a new piece of the molecular puzzle to the critically important regulators of fat development in mammalian organisms. We found the effect of Taf7l in adipogenesis to be quite robust wherein its loss led to extensive down-regulation of genome-wide adipocyte-specific gene expression in cell culture and defects in WAT development in vivo. We are particularly intrigued by the manner in which TAF7L seems to operate–serving both as an integral component of TFIID at the core promoter and as a key co-activator interacting directly with PPARγ or other adipocyte-specific transcriptional factors (ATFs) at proximal enhancers of adipocyte-specific genes on genome-wide scale (Figure 8). Thus, a hitherto unrecognized cell-type selective core regulator with an apparent dual mechanism of action has been identified that influences the pro-adipogenic transcriptional control network. It is conceivable that TAF7L and associated regulatory factors in this newly discovered pathway may reveal potentially useful therapeutic drug targets to combat obesity and its related diseases.10.7554/eLife.00170.014Figure 8.Dual functions of TAF7L in adipocyte differentiation.


Dual functions of TAF7L in adipocyte differentiation.

Zhou H, Kaplan T, Li Y, Grubisic I, Zhang Z, Wang PJ, Eisen MB, Tjian R - Elife (2013)

Dual functions of TAF7L in adipocyte differentiation.TAF7L expression is enriched during C3H10T1/2 MSCs adipocyte differentiation while other TFIID subunits (TAFs) decrease in expression. TAF7L regulates adipogenesis by associating with TBP as a component of adipocyte TFIID complex at promoters and with PPARγ or other adipocyte transcriptional factors (ATFs) as a cofactor at enhancers on adipocyte-specific genes, providing the mechanisms of its dual roles during differentiation. General highly-expressed genes are those with high expression before and after adipocyte differentiation include a portion of housekeeping genes; adipocyte-specific genes are those required for adipocyte differentiation and highly upregulated during adipocyte differentiation. TAFs,TBP-associated factors; ATFs, adipocyte transcriptional factors; BEs, binding elements.DOI:http://dx.doi.org/10.7554/eLife.00170.014
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3539393&req=5

fig8: Dual functions of TAF7L in adipocyte differentiation.TAF7L expression is enriched during C3H10T1/2 MSCs adipocyte differentiation while other TFIID subunits (TAFs) decrease in expression. TAF7L regulates adipogenesis by associating with TBP as a component of adipocyte TFIID complex at promoters and with PPARγ or other adipocyte transcriptional factors (ATFs) as a cofactor at enhancers on adipocyte-specific genes, providing the mechanisms of its dual roles during differentiation. General highly-expressed genes are those with high expression before and after adipocyte differentiation include a portion of housekeeping genes; adipocyte-specific genes are those required for adipocyte differentiation and highly upregulated during adipocyte differentiation. TAFs,TBP-associated factors; ATFs, adipocyte transcriptional factors; BEs, binding elements.DOI:http://dx.doi.org/10.7554/eLife.00170.014
Mentions: It is well-documented that the adult human body contains cells residing in the adipose tissue, referred to as Adipose-derived Stem Cells (ASCs) (DeLany et al., 2005; Feve, 2005; Gonzalez, 2005; Gerlach et al., 2012). ASCs resemble mesenchymal stem cells (MSCs) in terms of their ability to differentiate into multiple lineages including adipocytes, myotubes, osteocytes, and cartilage under appropriate developmental cues (Gornostaeva et al., 2006). Given that increased numbers of adipocytes, a major underlying cause of obesity, are primarily derived from MSCs and/or ASCs (Bowers and Lane, 2008), we chose C3H10T1/2 MSCs as our cell culture model system for studying adipogenesis in large measure because MSCs efficiently recapitulate aspects of adipocyte differentiation and in vivo fat development. Using this MSC culture model as well as Taf7l KO mouse model for our in vitro and in vivo studies, we unexpectedly identified Taf7l as a key regulator of adipogenesis; adding a new piece of the molecular puzzle to the critically important regulators of fat development in mammalian organisms. We found the effect of Taf7l in adipogenesis to be quite robust wherein its loss led to extensive down-regulation of genome-wide adipocyte-specific gene expression in cell culture and defects in WAT development in vivo. We are particularly intrigued by the manner in which TAF7L seems to operate–serving both as an integral component of TFIID at the core promoter and as a key co-activator interacting directly with PPARγ or other adipocyte-specific transcriptional factors (ATFs) at proximal enhancers of adipocyte-specific genes on genome-wide scale (Figure 8). Thus, a hitherto unrecognized cell-type selective core regulator with an apparent dual mechanism of action has been identified that influences the pro-adipogenic transcriptional control network. It is conceivable that TAF7L and associated regulatory factors in this newly discovered pathway may reveal potentially useful therapeutic drug targets to combat obesity and its related diseases.10.7554/eLife.00170.014Figure 8.Dual functions of TAF7L in adipocyte differentiation.

Bottom Line: Depletion of TAF7L reduced adipocyte-specific gene expression, compromised adipocyte differentiation, and WAT development as well.Genome-wide mRNA-seq expression profiling and ChIP-seq binding studies confirmed that TAF7L is required for activating adipocyte-specific genes via a dual mechanism wherein it interacts with PPARγ at enhancers and TBP/Pol II at core promoters.In vitro binding studies confirmed that TAF7L forms complexes with both TBP and PPARγ.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology , Howard Hughes Medical Institute, University of California, Berkeley , Berkeley , United States ; Li Ka Shing Center For Biomedical and Health Sciences, CIRM Center of Excellence, University of California, Berkeley , Berkeley , United States.

ABSTRACT
The diverse transcriptional mechanisms governing cellular differentiation and development of mammalian tissue remains poorly understood. Here we report that TAF7L, a paralogue of TFIID subunit TAF7, is enriched in adipocytes and white fat tissue (WAT) in mouse. Depletion of TAF7L reduced adipocyte-specific gene expression, compromised adipocyte differentiation, and WAT development as well. Ectopic expression of TAF7L in myoblasts reprograms these muscle precursors into adipocytes upon induction. Genome-wide mRNA-seq expression profiling and ChIP-seq binding studies confirmed that TAF7L is required for activating adipocyte-specific genes via a dual mechanism wherein it interacts with PPARγ at enhancers and TBP/Pol II at core promoters. In vitro binding studies confirmed that TAF7L forms complexes with both TBP and PPARγ. These findings suggest that TAF7L plays an integral role in adipocyte gene expression by targeting enhancers as a cofactor for PPARγ and promoters as a component of the core transcriptional machinery.DOI:http://dx.doi.org/10.7554/eLife.00170.001.

No MeSH data available.


Related in: MedlinePlus