![]() ![]() We found that the chromatin remodeler Chd1 is an essential regulator of hypertranscription in stem cells that acts to promote repair of DNA breaks that accumulate at the promoters of protein coding genes and rDNA ( Bulut-Karslioglu Nature Communications 2021). We are using both cell culture and mouse models to further investigate the molecular regulation of hypertranscription in stem/progenitor cells during embryonic development and in adulthood. We found that hypertranscription is critical for the growth of pluripotent cells at the time of implantation and for the expansion of definitive hematopoietic stem cells ( Percharde Cell Rep 2017, Guzman-Ayala Development 2015, Koh Proc Natl Acad Sci USA 2015). Hypertranscription, the global amplification of the transcriptome, is pervasive in stem/progenitor cells but has remained largely undetected until recently due to technical and analytic limitations that can now be overcome ( read our review on this topic). ![]() However, we have found that this assumption is incorrect in many settings, notably during development. The general assumption is that the overall level of the transcriptome does not change much between different cell types, and only a relatively small set of “outlier” genes that change in activity between cell types (so-called tissue-specific genes) are of interest. The part of the genome that is activated, that is, transcribed into RNA, in any given cell, is called the transcriptome. Our research is organized around 3 principal avenues of inquiry, each of which has several points of synergy with the other avenues. Recent work from our lab highlights that such foundational aspects as genome organization, transcription and environmental input are regulated in unique and novel ways in pluripotent cells of the early embryo and the germline. Of particular interest are pluripotent cells that exist in the mammalian embryo and give rise to all cell types of the body. Our lab is interested in understanding the genome-environment interactions that shape mammalian development and reproduction. While development is often approached as simply hardwired in the genome, there is a growing appreciation that the environment provides key inputs into the bookmarking and activation of the genome during ontogeny, but such inputs remain very poorly understood at the mechanistic level. With each generation, the precise spatio-temporal unfolding of embryonic development requires a tight orchestration of dynamic changes in chromatin states and corresponding transcriptional programs. ![]()
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