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DDB1 Binds Histone Reader BRWD3 to Activate the Transcriptional Cascade in Adipogenesis and Promote Onset of Obesity (RNA-Seq)

ABSTRACT: DDB1 is typically recognized as a component of the Cullin4 (CUL4)-RING E3 ubiquitin ligase complex. Here, we show that DDB1 functions independently of CUL4 to promote adipogenesis and diet-induced obesity. In contrast to depletion of CUL4A or CUL4B that stimulates adipogenesis, lack of DDB1 dramatically suppresses the process. Re-introduction of a DDB1 mutant that lacks the binding ability to CUL4A or CUL4B fully restores adipogenesis in DDB1-deficient preadipocytes. Furthermore, while inducibly knocking out Cul4a or Cul4b in mice aggravates diet-induced obesity, Ddb1+/- mice are lean on high-fat diet. Mechanistically, by binding the bromodomain-containing histone reader BRWD3, DDB1 is recruited to acetylated histones in the proximal promoters of immediate-early response genes, where it facilitates the release of paused RNA polymerase II (Pol II) and activates the transcription of these genes. Our findings have thus uncovered a mechanism of activating the transcriptional cascade in adipogenesis by DDB1-mediated release of paused Pol II.

ORGANISM(S): Mus musculus

PROVIDER: GSE158172 | GEO | 2023/09/17

REPOSITORIES: GEO

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DDB1 Binds Histone Reader BRWD3 to Activate the Transcriptional Cascade in Adipogenesis and Promote Onset of Obesity (ChIP-Seq)

Project description:DDB1 is typically recognized as a component of the Cullin4 (CUL4)-RING E3 ubiquitin ligase complex. Here, we show that DDB1 functions independently of CUL4 to promote adipogenesis and diet-induced obesity. In contrast to depletion of CUL4A or CUL4B that stimulates adipogenesis, lack of DDB1 dramatically suppresses the process. Re-introduction of a DDB1 mutant that lacks the binding ability to CUL4A or CUL4B fully restores adipogenesis in DDB1-deficient preadipocytes. Furthermore, while inducibly knocking out Cul4a or Cul4b in mice aggravates diet-induced obesity, Ddb1+/- mice are lean on high-fat diet. Mechanistically, by binding the bromodomain-containing histone reader BRWD3, DDB1 is recruited to acetylated histones in the proximal promoters of immediate-early response genes, where it facilitates the release of paused RNA polymerase II (Pol II) and activates the transcription of these genes. Our findings have thus uncovered a mechanism of activating the transcriptional cascade in adipogenesis by DDB1-mediated release of paused Pol II.

2023-09-17 | GSE158171 | GEO

DDB1 Binds Histone Reader BRWD3 to Activate the Transcriptional Cascade in Adipogenesis and Promote Onset of Obesity (ChIP-seq II)

2023-09-17 | GSE168136 | GEO

The Mediator Subunit MED20 Organizes the Early Adipogenic Complex to Promote Development of Adipose Tissues and Diet-Induced Obesity

Project description:MED20 is a non-essential subunit of the transcriptional coactivator Mediator complex, but its physiological function remains largely unknown. Here we show that MED20 plays a key role in the development of adipose tissue and diet-induced obesity. Through affinity purification and candidate screening, we demonstrate that MED20 is targeted for degradation by the anti-obesity CRL4-WDTC1 E3 complex. Depleting MED20 in either 3T3-L1 cells or primary preadipocytes inhibits adipogenesis. Mice with MED20 knocked out in preadipocytes show dramatic defect in the development of brown adipose tissue. Furthermore, removing one allele of Med20 in preadipocytes protects mice from diet-induced obesity, and reverses weight gain in Cul4a- or Cul4b-depleted mice. Mechanistically, MED20 plays a key role in organizing the early adipogenic complex by bridging C/EBPβ and RNA polymerase II and thereby stimulating the transcription of PPARγ. Our study has thus identified MED20 as a potential target for obesity treatment.

2023-12-15 | GSE163281 | GEO

The CRL4B E3 ubiquitin ligase complex regulates mitosis by recruiting phospho-specific DCAFs

Project description:The cullin scaffolds CUL4A and CUL4B assemble E3-ligase complexes regulating multiple mostly chromatin-associated cellular functions. Although they are structurally similar, we found that the unique N-terminal extension of CUL4B is heavily phosphorylated during mitosis, and this pattern is perturbed in CUL4B-P50L XLID patients. Indeed, phenotypic characterization and mutational analysis revealed that CUL4B phosphorylation is required for efficient progression through mitosis, controlling spindle positioning and cortical tension. Interestingly, while CUL4B phosphorylation triggers chromatin exclusion, it also promotes binding to actin regulators and two unconventional DCAFs, LIS1 and WDR1. Indeed, LIS1 and WDR1 directly bind DDB1, but their binding is enhanced by phosphorylation-dependent interactions with the unique amino terminal domain of CUL4B. Together, our studies uncover specific functions of CRL4B in mitosis, and identify previously unrecognized DCAFs that bind CUL4B by a phosphorylation-dependent mechanism.

2023-06-15 | PXD035329 | Pride

Transcriptome and analysis of Wdr70 deletion by next-generation sequencing

Project description:CRL4 is a family of SCF-like ubiquitin ligase constituted by Cul4-Ddb1-RING finger scaffold and DCAF substrate adaptors. We revealed Wdr70 as a novel DCAF protein that assembles with Cul4-Ddb1 and functions as chromatin remodeling factor in Schizosaccharomyces pombe.Besides its function in DNA repair, CRL4Wdr70 is speculated to regulate gene expression in a subset of yeast transcriptome. Here we use the next-generation sequencing to show that deletion of Wdr70 gene disturbs the gene expression profile of G2-synchronised yeast cells. Examination of genome-wide gene expression in 2 different yeast strains using Illumina Hiseq2500.

2016-04-04 | E-GEOD-79830 | biostudies-arrayexpress

Stably-paused genes revealed through inhibition of transcription initiation by the TFIIH inhibitor Triptolide

Project description:Transcription by RNA Polymerase II (Pol II) in metazoan is regulated in several steps, including preinitiation complex (PIC) formation, initiation, Pol II escape, productive elongation, cotranscriptional RNA-processing and termination. Genome-wide studies have demonstrated that the phenomenon of promoter-bound Pol II pausing is widespread, especially for genes involved in developmental and stimulus-responsive pathways. However, a mechanistic understanding of the paused Pol II states at promoters is limited. For example, at a global level, it’s unclear to what extent the engaged paused Pol II is stably tethered to the promoter or undergoes rapid cycles of initiation and termination. Here we used the small molecule Triptolide (TPL), an XPB/TFIIH inhibitor, to block transcriptional initiation followed by measuring Pol II occupancy by ChIP-seq. This inhibition of initiation enables us to investigate different states of paused Pol II. Specifically, our global analysis reveals that most genes with paused Pol II, as defined by pausing index, show significant clearance of Pol II during the period of TPL treatment. Our study further identifies a group of genes with unexpectedly stably-paused Pol II, with unchanged Pol II occupancy even after one hour of inhibition of initiation. This group of genes constitutes a small portion of all paused genes defined by the conventional criterion of pausing index. These findings could pave the way for evaluating the contribution of different elongation/pausing factors on different states of Pol II pausing in developmental and other stimulus-responsive pathways. ChIP-Seq of total/Ser5P Pol II in HCT116 cells treated with DMSO or TPL in serum starvation/activation or normal conditions. Nascent RNA-seq in HCT116 cells treated with DMSO or TPL in starved condition.

2015-01-05 | E-GEOD-63314 | biostudies-arrayexpress

The E3 ubiquitin ligase DDB1 controls homeostasis of hematopoietic stem and progenitor cells

Project description:Hematopoietic stem cells (HSC) are regulated to keep the balance between self-renewal and differentiation. However, little is known about post-translational regulations in HSCs. In this study, we characterize the role of DDB1, a component of the Cul4A-DDB1 E3 ubiquitin ligase complex, in HSCs and progenitors by using conditional DDB1 knockout models. We show that the maintenance and differentiation of both adult and fetal HSCs and progenitor cells is dependent on DDB1 function. Deletion of DDB1 alters cell cycle progression and induces apoptosis. Furthermore, deletion of DDB1 in developing thymocytes had no effects on T cell differentiation, whereas DDB1-deficient peripheral T cells were not able to enter cell cycle when stimulated in vitro. In addition, DDB1 is essential for T cell leukemia initiation. Our results reveal that DDB1 is required for adult and fetal hematopoiesis as it controls progenitor and stem cell homeostasis. Transcriptional consequences of inactivating DDB1 in fetal LSK cells. Four samples were analyzed: wild-type (WT) control and DDB1-deficient (DDB1) Lin-ckit+Sca1+ (LSK) cells sorted from fetal livers E16.5 of DDB1 flox/flox, VavCre+ and control mice.

2015-07-10 | E-GEOD-70658 | biostudies-arrayexpress

PAF1 regulation of promoter-proximal pause release via enhancer activation

Project description:Gene expression in metazoans is regulated by RNA Polymerase II (Pol II) promoter-proximal pausing and its release. Previously, we identified that Pol II-associated factor 1 (PAF1) modulates the release of paused Pol II into productive elongation. Here, we find that PAF1 occupies transcriptional enhancers and restrains hyperactivation of a subset of these enhancers. Enhancer activation as the result of Paf1 loss releases Pol II from paused promoters of nearby PAF1 target genes. Knockout of PAF1-regulated enhancers attenuates the release of paused Pol II on PAF1 target genes without major interference in the establishment of pausing at their cognate promoters. Thus, a subset of enhancers can primarily modulate gene expression by controlling the release of paused Pol II in a PAF1-dependent manner.

2017-09-01 | GSE97527 | GEO

Stably-paused genes revealed through inhibition of transcription initiation by the TFIIH inhibitor Triptolide

2015-01-05 | GSE63314 | GEO

RNA Polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA Polymerase II

Project description:Release of promoter-proximal paused RNA polymerase II (Pol II) during early elongation is a critical step in transcriptional regulation in metazoan cells. Paused Pol II release is thought to require the kinase activity of cyclin-dependent kinase 9 (CDK9) for the phosphorylation of DRB sensitivity-inducing factor, negative elongation factor, and C-terminal domain (CTD) serine-2 of Pol II. We found that Pol II-associated factor 1 (PAF1) is a critical regulator of paused Pol II release, that positive transcription elongation factor b (P-TEFb) directly regulates the initial recruitment of PAF1 complex (PAF1C) to genes, and that the subsequent recruitment of CDK12 is dependent on PAF1C. These findings reveal cooperativity among P-TEFb, PAF1C, and CDK12 in pausing release and Pol II CTD phosphorylation. Comparison of the chromatin occupancy of [1] PAF1, CDC73, LEO1, CTR9, total Pol II, and CTD serine 2-phosphorylated Pol II by ChIP-seq in THP1 cells; [2] PAF1, Pol II, Pol II (ser-5p), CDK12, and CDK9 by ChIP-seq in control and PAF1 knockdown cells; [3] LEO1 and Pol II by ChIP-seq in control and flavopiridol treated THP1 cells.

2015-12-11 | E-GEOD-62171 | biostudies-arrayexpress

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