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Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities

ABSTRACT: Genome-scale studies have revealed extensive co-localization of transcription factors in a given cell type as well as substantial differences in the binding patterns of specific transcription factors between cell types. Several mechanisms have been proposed to explain these observations, including targeting of transcription factors to accessible chromatin marked by lysine 4-monomethylated histone H3 (H3K4me1) and interactions between transcription factors that enable nucleosome displacement. Here we demonstrate that collaborative interactions of PU.1 with small sets of macrophage- or B cell-lineage-determining transcription factors establish common and cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions in macrophages and B cells, respectively. PU.1 binding initiates nucleosome remodeling followed by H3K4 monomethylation at large numbers of genomic regions associated with both broadly and specifically expressed genes. These sites are representative of locations that serve as beacons for additional factors, exemplified by liver X receptors, which drive both cell-specific gene expression and signal-dependent responses. In concert with analysis of transcription factor binding and H3K4me1 patterns in other cell types, these studies suggest that simple combinations of lineage-determining transcription factors can specify the genomic sites ultimately responsible for both cell identity and cell type-specific responses to diverse signaling inputs.

ORGANISM(S): Mus musculus

PROVIDER: GSE21512 | GEO | 2010/05/27

SECONDARY ACCESSION(S): PRJNA125987

REPOSITORIES: GEO

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Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities

Project description:Genome-scale studies have revealed extensive co-localization of transcription factors in a given cell type as well as substantial differences in the binding patterns of specific transcription factors between cell types. Several mechanisms have been proposed to explain these observations, including targeting of transcription factors to accessible chromatin marked by lysine 4-monomethylated histone H3 (H3K4me1) and interactions between transcription factors that enable nucleosome displacement. Here we demonstrate that collaborative interactions of PU.1 with small sets of macrophage- or B cell-lineage-determining transcription factors establish common and cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions in macrophages and B cells, respectively. PU.1 binding initiates nucleosome remodeling followed by H3K4 monomethylation at large numbers of genomic regions associated with both broadly and specifically expressed genes. These sites are representative of locations that serve as beacons for additional factors, exemplified by liver X receptors, which drive both cell-specific gene expression and signal-dependent responses. In concert with analysis of transcription factor binding and H3K4me1 patterns in other cell types, these studies suggest that simple combinations of lineage-determining transcription factors can specify the genomic sites ultimately responsible for both cell identity and cell type-specific responses to diverse signaling inputs. ChIP-Seq and gene expression profiling was performed in macrophages, B cells, and a variety of genetically modified primary cells and cell lines approximating developmental stages of macrophage and B cell development.

2010-05-27 | E-GEOD-21512 | biostudies-arrayexpress

Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages

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2010-03-05 | E-GEOD-19553 | biostudies-arrayexpress

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Mechanisms of PU.1 binding site selection in-vivo

2013-05-15 | GSE43098 | GEO

Identification and Characterization of Enhancers Controlling the Inflammatory Gene Expression Program in Macrophages

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The hematopoietic master transcription factor PU.1 requires its interaction with the SWI/SNF remodeler to access chromatin de novo

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2019-11-20 | PXD013167 | Pride

Genome-wide maps of histone modification in WT and MLL4-/- during brown preadipocyte differentiation

Project description:Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for the deposition of H3K4me1/2 on enhancers remain elusive. Furthermore, the functions of these methyltransferases on enhancers and associated cell-type-specific gene expression are poorly understood. Here, we identify MLL4 (KMT2D) as a major H3K4 mono- and di-methyltransferase in mammalian cells. Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of MLL4 dramatically decreases H3K4me1/2 and H3K27ac on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Finally, we provide evidence that lineage-determining TFs recruit and require MLL4 to establish enhancers critical for cell-type-specific gene expression. Together, these results identify MLL4 as an H3K4 mono-/di-methyltransferase required for enhancer activation during cell differentiation. ChIP-Seq analyses of histone modifications (H3K4me1, H3K4me2, H3K4me3, and H3K27ac) at D0 (day 0) and D2 (day 2) of adipogenesis in WT (MLL3-/-) and MLL4 KO (MLL3-/-;MLL4-/-) brown preadipocytes.

2013-12-17 | E-GEOD-50417 | biostudies-arrayexpress

Genome-wide maps of C/EBPbeta, MLL4 and histone modifications in C/EBPbeta-overexpressed WT and MLL4-/- brown preadipocytes

Project description:Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for the deposition of H3K4me1/2 on enhancers remain elusive. Furthermore, the functions of these methyltransferases on enhancers and associated cell-type-specific gene expression are poorly understood. Here, we identify MLL4 (KMT2D) as a major H3K4 mono- and di-methyltransferase in mammalian cells. Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of MLL4 dramatically decreases H3K4me1/2 and H3K27ac on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Finally, we provide evidence that lineage-determining TFs recruit and require MLL4 to establish enhancers critical for cell-type-specific gene expression. Together, these results identify MLL4 as an H3K4 mono-/di-methyltransferase required for enhancer activation during cell differentiation. ChIP-Seq analyses of C/EBPbeta, MLL4 and histone modifications (H3K4me1, H3K27ac) in vec- or C/EBPbeta-overexpressing, adenoviral GFP- or Cre-infected, MLL3-/-MLL4-flox/flox brown preadipocytes without induction of differentiation.

2013-12-17 | E-GEOD-50455 | biostudies-arrayexpress

ETS trancription factors PU.1 and Spi-B binding in mouse lymphoma cells

Project description:Spi-B and PU.1 are highly related members of the E26-transformation-specific (ETS) family of transcription factors that have similar, but not identical, functions in B cell development. PU.1 and Spi-B are both expressed at high levels in lymphoma cell lines. We hypothesized that Spi-B and PU.1 occupy similar sites in the genome. To determine binding sites of Spi-B and PU.1, WEHI-279 mouse lymphoma cells were infected with retroviral vectors encoding 3XFLAG-tagged PU.1 or Spi-B. Anti-FLAG chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) was performed. Both transcription factors occupied approximately 2000 sites in the genome, and approximately half of these sites were bound by both factors while the other sites were unique to each factor.

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Pruning of the adipocyte cistrome by hematopoietic master regulator PU.1 (expression)

Project description:Master transcription factors are the gatekeepers of lineage identity. As such, they have been a major focus of efforts to manipulate cell fate for therapeutic purposes. The ETS transcription factor PU.1 has a potent ability to confer macrophage phenotypes on cells already committed to a different lineage, but how it overcomes the presence of other master regulators is not known. The nuclear receptor PPARγ is the master regulator of the adipose lineage, and its genomic binding pattern is well characterized in adipocytes. Here, we show that when expressed at macrophage levels in mature adipocytes, PU.1 bound a large fraction of its macrophage sites, where it induced chromatin opening and the expression of macrophage target genes. Strikingly, PU.1 markedly reduced the genomic binding of PPARγ without changing its abundance. PU.1 expression repressed genes with nearby adipocyte-specific PPARγ binding sites, while a common macrophage-adipocyte gene expression program was retained. Together, these data reveal unexpected lability within the adipocyte PPARγ cistrome and show that even in terminally differentiated cells, PU.1 can remodel the cistrome of another master regulator.

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