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FBXL19 transcriptionally primes promoters of developmental genes via CDK8-Mediator recruitment [RNA-seq]

ABSTRACT: Regulatory elements called CpG islands (CGIs) are associated with the majority of mammalian gene promoters and have been proposed to play an important role in gene expression. The regulatory capacity of CGIs is thought to rely upon a family of proteins that recognise CGIs through their ZF-CxxC DNA binding domains to recruit chromatin-modifying activities to gene promoters. Through studying FBXL19, a poorly characterized ZF-CxxC domain-containing protein, we have discovered that it specifically interacts with the CDK8-Mediator complex in mouse embryonic stem cells (ESCs). Intriguingly, FBXl19 recruits CDK8-Mediator to a subset of CGI-associated promoters of repressed developmental genes in ESCs. We show that FBXL19-dependent recruitment of CDK8 in ESCs is required for the proper induction of the associated genes during ESC differentiation. This is consistent with early embryonic lethality of in FBXl19 deficient mice. Together, our observations highlight a novel role for FBXL19 in priming developmental gene expression, via recruitment of CDK8 to their CGI promoters, in order to support normal gene induction during differentiation and development.

ORGANISM(S): Mus musculus

PROVIDER: GSE98755 | GEO | 2018/06/08

REPOSITORIES: GEO

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FBXL19 transcriptionally primes promoters of developmental genes via CDK8-Mediator recruitment [ChIP-seq 1]

Project description:Regulatory elements called CpG islands (CGIs) are associated with the majority of mammalian gene promoters and have been proposed to play an important role in gene expression. The regulatory capacity of CGIs is thought to rely upon a family of proteins that recognise CGIs through their ZF-CxxC DNA binding domains to recruit chromatin-modifying activities to gene promoters. Through studying FBXL19, a poorly characterized ZF-CxxC domain-containing protein, we have discovered that it specifically interacts with the CDK8-Mediator complex in mouse embryonic stem cells (ESCs). Intriguingly, FBXl19 recruits CDK8-Mediator to a subset of CGI-associated promoters of repressed developmental genes in ESCs. We show that FBXL19-dependent recruitment of CDK8 in ESCs is required for the proper induction of the associated genes during ESC differentiation. This is consistent with early embryonic lethality of in FBXl19 deficient mice. Together, our observations highlight a novel role for FBXL19 in priming developmental gene expression, via recruitment of CDK8 to their CGI promoters, in order to support normal gene induction during differentiation and development.

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FBXL19 transcriptionally primes promoters of developmental genes via CDK8-Mediator recruitment [ChIP-seq 2]

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Fbxl19 recruits Rnf20 to CpG Islands and promotes H2B mono-ubiquitination [Affymetrix]

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Fbxl19 recruits Rnf20 to CpG Islands and promotes H2B mono-ubiquitination [ChIP-Seq]

Project description:Rnf20 catalyzes lysine 120 mono-ubiquitination of histone H2B (H2Bub1) that has been previously invloved in normal differentiation of embryonic stem (ES) and adult stem cells. However,the mechanims underlying by which Rnf20 is recruited to its target chromosomal loci to generate H2Bub1 is still elusive. Here, we reveal that Fbxl19, a CxxC domain-containing protein, physically interacts with Rnf20, guides it preferentially to CpG island-containing target promoters, and thereby promotes mono-ubiqutination of H2B. We first show that up-regulation of Fbxl19 induces the level of global H2Bub1, while down-regulation of Fbxl19 reduces the level of H2Bub1 in mouse ES cells. Our genome-wide target mapping unveils the preferential occupancy of Fbxl19 on CpG island-containing promoters, and we further show that the binding of Fbxl19 is essential for the recruitment of Rnf20 to its target genes and subsequent H2Bub1. Altogether, our results demonstrate that Fbxl19 plays critical roles in the H2Bub1 pathway by recruiting Rnf20 to CGI target genes specifically and selectively.

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CDK-Mediator and FBXL19 cooperate in the induction of developmental genes by promoting regulatory interactions [CaptureC]

Project description:Appropriate developmental gene regulation relies on the capacity of gene promoters to integrate inputs from distal regulatory elements, yet how this is achieved remains poorly understood. In embryonic stem cells (ESCs), a subset of silent developmental gene promoters are primed for activation by FBXL19, a CpG island binding protein, through its capacity to recruit CDK-Mediator. How mechanistically these proteins function together to prime genes for activation during differentiation is unknown. Here we discover that in mouse ESCs FBXL19 and CDK-Mediator support long-range interactions between silent gene promoters that rely on FBXL19 for their induction during differentiation and gene regulatory elements. During gene induction, these distal regulatory elements behave in an atypical manner, in that the majority do not acquire histone H3 lysine 27 acetylation and no longer interact with their target gene promoter following gene activation. Despite these atypical features, we demonstrate by targeted deletions that these distal elements are required for appropriate gene induction during differentiation. Together these discoveries demonstrate that CpG-island associated gene promoters can prime genes for activation by communicating with atypical distal gene regulatory elements to achieve appropriate gene expression.

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CDK-Mediator and FBXL19 cooperate in the induction of developmental genes by promoting regulatory interactions [Native ChIP-seq]

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A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer

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