The part of the genome that is activated, that is, transcribed into RNA, in any given cell, is called the transcriptome. 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. However, we have found that this assumption is incorrect in many settings, notably during development.
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). 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). 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 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). In parallel, we developed methods to detect hypertranscription in single-cell RNA-seq data, and found that hypertranscription is remarkably pervasive in stem/progenitor cells across all major adult organs (Kim Cell Reports 2023). Our results indicate that hypertranscription is a general and dynamic cellular program that is recurrently employed during development, organ maintenance and regeneration.
We are also dissecting the regulation of open chromatin and hypertranscription in a systematic manner, using genome-wide screens in Embryonic Stem (ES) cells. The results of one such screen, reveal that the permissive chromatin state and hypertranscription of pluripotent stem cells are acutely tuned to their translational capacity, itself dependent on nutrient availability. This work led to the discovery of a paused pluripotent state in mouse ES cells and blastocysts, induced by mTor inhibition (Bulut-Karslioglu Nature 2016). This state of “suspended animation” models one that occurs in wild animals, called diapause, whereby blastocysts reversibly arrest development during periods of unfavorable environmental conditions. The ability to reversibly suspend the development of a mammal in the laboratory, and to mimic such developmental pausing in ES cells, offers a tractable model to dissect a number of fascinating questions. We have discovered that RNA methylation is critical to maintain the paused state, and identified the underlying mechanisms. Our results (Collignon Nature Cell Biology 2023) reveal that an intricate cross-talk between transcriptional and post-transcriptional layers of gene regulation ensures that cells remain dormant but viable during diapause. We are interested in understanding the interplay between environment, chromatin, and hypertranscription in the decision between cell activation vs dormancy in development and disease (see also Environment-epigenome interactions). Working with our collaborators in Toronto, we have found that cancer cells highjack the same molecular and cellular pathways of diapause to survive chemotherapy in a dormant state so that they can later regrow tumors (Rehman Cell 2021). The results point to new strategies to target these dormant cancer cells.
