Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities

Abstract

Summary Genome-scale studies have revealed extensive, cell type-specific co-localization of transcription factors, but the mechanisms underlying this phenomenon remain poorly understood. Here we demonstrate in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B celllineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions. 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 locations serve as beacons for additional factors, exemplified by liver X receptors, which drive both cell-specific gene expression and signal-dependent responses. Together with analyses 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.

JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

“…Among them are YY1 and E2F3, which show increased motif activity upon JQ1 treatment, and LEF1, FOSL1, and ZNF281, which show decreased motif activity (Figure 6(A)). To further refine TF candidates into BRD2-dependent or independent pathways, we performed motif search analysis by HOMER [33] using BRD2 binding sites of JQ1-upregulated and downregulated promoters. The downregulated promoters were enriched in ZNF281-binding motifs (Figure 6(B), left), while E2F4- and YY1-binding motifs were enriched in the upregulated promoters (Figure 6(B), right).…”

“…Since LEF1- and FOSL1-binding motifs were not identified in the downregulated genes, they may be involved in the non-BRD2 regulatory pathway. Indeed, our HOMER [33] motif enrichment analysis identified that LEF1- and FOSL1-binding motifs were enriched within H4K5acK8ac peaks without BRD2 binding (Figure 6(C), left). Examples of promoters without BRD2 are shown in Fig.…”

“…S2A), was determined using peak annotation function of HOMER [33]. To examine and visualize enrichment of histone modification marks or BRD2 in defined regions, such as promoter, enhancer, eRNA, we performed meta-region analysis using genomation [69].…”

Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

“…H3K27ac data of the samples within the same subgroup were combined. For each subgroup, nucleosome free regions (NFRs) were identified using the “findPeaks” function of HOMER 26 (http://homer.salk.edu/homer/ngs/index.html) with option “-nfr”. ENCODE transcription factor motifs and their mapped positions in the genome were downloaded from http://compbio.mit.edu/encode-motifs/.…”

Cell type-specific DNA methylation in neonatal cord tissue and cord blood: a 850K-reference panel and comparison of cell types

“…We further examined the variable CpGs (with DNA methylation IQR ≥ 5%) in terms of their genomic features (promoter, 5ʹ-UTR, exon, intron, 3ʹ-UTR, TTS, and intergenic) and CpG content (island, shores, shelves, open seas). Genomic features of the CpGs were annotated using Homer annotatePeaks function (hg19) [33]. …”