Abstract
Mapping the chromatin occupancy of transcription factors (TFs) is a key step in deciphering developmental transcriptional programs. Here we use biotinylated knockin alleles of seven key cardiac TFs (GATA4, NKX2-5, MEF2A, MEF2C, SRF, TBX5, TEAD1) to sensitively and reproducibly map their genome-wide occupancy in the fetal and adult mouse heart. These maps show that TF occupancy is dynamic between developmental stages and that multiple TFs often collaboratively occupy the same chromatin region through indirect cooperativity. Multi-TF regions exhibit features of functional regulatory elements, including evolutionary conservation, chromatin accessibility, and activity in transcriptional enhancer assays. H3K27ac, a feature of many enhancers, incompletely overlaps multi-TF regions, and multi-TF regions lacking H3K27ac retain conservation and enhancer activity. TEAD1 is a core component of the cardiac transcriptional network, co-occupying cardiac regulatory regions and controlling cardiomyocyte-specific gene functions. Our study provides a resource for deciphering the cardiac transcriptional regulatory network and gaining insights into the molecular mechanisms governing heart development.
Highlights
Mapping the chromatin occupancy of transcription factors (TFs) is a key step in deciphering developmental transcriptional programs
Mef2c null mice died by embryonic day 10 (E10) with two chambered hearts that failed to undergo normal looping[9], indicating that Mef2c fb is hypomorphic but sufficient to support most aspects of fetal heart development
The preferred motifs were significantly over-represented adjacent to a subset of these differentially expressed genes (DEGs), suggesting that these preferred motifs have increased regulatory activity. These analyses indicate that TEAD1 is an integral component of the cardiac transcriptional regulatory network and that it regulates core cardiomyocyte-specific functions including contraction and metabolism
Summary
Mapping the chromatin occupancy of transcription factors (TFs) is a key step in deciphering developmental transcriptional programs. We previously showed that pull-down of biotinylated TFs and associated chromatin followed by generation sequencing (bioChIP-seq) sensitively and reproducibly maps TF occupancy, both in cultured cells and in mouse tissues[3,4,15,16] We extend this approach to map the genome-wide occupancy of seven TFs (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, and TEAD1) in fetal and adult heart, providing a valuable resource for the study of cardiac transcriptional regulation. Our analyses of these data identify regions bound by multiple TFs and show that these regions are transcriptional regulatory elements that function both in the presence and absence of the activating histone mark H3K27ac
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
