Distant cis-regulatory elements in human skeletal muscle differentiation

Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Genomics (Impact Factor: 2.28). 08/2011; 98(6):401-11. DOI: 10.1016/j.ygeno.2011.08.003
Source: PubMed

ABSTRACT Identifying gene regulatory elements and their target genes in human cells remains a significant challenge. Despite increasing evidence of physical interactions between distant regulatory elements and gene promoters in mammalian cells, many studies consider only promoter-proximal regulatory regions. We identify putative cis-regulatory modules (CRMs) in human skeletal muscle differentiation by combining myogenic TF binding data before and after differentiation with histone modification data in myoblasts. CRMs that are distant (>20 kb) from muscle gene promoters are common and are more likely than proximal promoter regions to show differentiation-specific changes in myogenic TF binding. We find that two of these distant CRMs, known to activate transcription in differentiating myoblasts, interact physically with gene promoters (PDLIM3 and ACTA1) during differentiation. Our results highlight the importance of considering distal CRMs in investigations of mammalian gene regulation and support the hypothesis that distant CRM-promoter looping contacts are a general mechanism of gene regulation.

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    • "He et al. (2011) used a set of five cardiac-specific transcription factors to identify cardiac-specific enhancers that were distinct from p300 bound enhancers. Analysis of the binding of a set of three myogenic-specific transcription factors in combination with p300 binding and enhancer-associated chromatin marks before and after muscle differentiation allowed for the identification of muscle-specific enhancers (McCord et al., 2011). Furthermore, the mysterious highly occupied target (HOT) regions which are bound by many transcription factors but lack their consensus binding motif, function as spatial and temporal enhancers in transgenic assays (Kvon et al., 2012). "
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