Intrinsic Specificity of Binding and Regulatory Function of Class II bHLH Transcription Factors




Casey, Bradford Harris

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Embryonic development begins with a single cell, and gives rise to the many diverse cells which comprise the complex structures of the adult animal. Distinct cell fates require precise regulation to develop and maintain their functional characteristics. Transcription factors provide a mechanism to select tissue-specific programs of gene expression from the shared genome. ASCL1, ASCL2, and MYOD are class II basic Helix-Loop-Helix (bHLH) transcription factors which play crucial roles in lineage specification in the developing embryo. In vivo, these factors bind to distinct genomic sites, and regulate distinct transcriptional programs. The mechanisms by which they select their cognate binding sites remain poorly defined. Here, we utilize an inducible system to express these master regulatory factors in embryonic stem cells to characterize early events in bHLH factor binding and function in a common cellular context, removed from their role as endogenous master regulators of lineage specification. Using genome-wide sequencing approaches, we demonstrate that these factors maintain distinct binding when ectopically expressed in a common context. We observe that they initiate distinct transcriptional programs, which include key regulators in lineage specification. By comparing chromatin accessibility of bHLH binding sites, we reveal a shared ability for these factors to bind nucleosome-occupied sites, and meet the criteria which define pioneer transcription factors. We further characterize epigenetic features of the empirically observed genome-wide binding sites of these factors, and compare these findings to the conventional understanding of bHLH factor function. This work represents the first comprehensive approach to direct comparison of early events in the binding and transcriptional profiles of ASCL1, ASCL2, and MYOD.

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