Allele-specific differential regulation of monoallelically expressed autosomal genes in the cardiac lineage

Each mammalian autosomal gene is represented by two alleles in diploid cells. To our knowledge, no insights have been made in regard to allele-specific regulatory mechanisms of autosomes. Here we use allele-specific single cell transcriptomic analysis to elucidate the establishment of monoallelic gene expression in the cardiac lineage. We find that monoallelically expressed autosomal genes in mESCs and mouse blastocyst cells are differentially regulated based on the genetic background of the parental alleles. However, the genetic background of the allele does not affect the establishment of monoallelic genes in differentiated cardiomyocytes. Additionally, we observe epigenetic differences between deterministic and random autosomal monoallelic genes. Moreover, we also find a greater contribution of the maternal versus paternal allele to the development and homeostasis of cardiac tissue and in cardiac health, highlighting the importance of maternal influence in male cardiac tissue homeostasis. Our findings emphasize the significance of allele-specific insights into gene regulation in development, homeostasis and disease

An FGFR1-SPRY2 Signaling Axis Limits Basal Cell Proliferation in the Steady-State Airway Epithelium.

The steady-state airway epithelium has a low rate of stem cell turnover but can nevertheless mount a rapid proliferative response following injury. This suggests a mechanism to restrain proliferation at steady state. One such mechanism has been identified in skeletal muscle in which pro-proliferative FGFR1 signaling is antagonized by SPRY1 to maintain satellite cell quiescence. Surprisingly, we found that deletion of Fgfr1 or Spry2 in basal cells of the adult mouse trachea caused an increase in steady-state proliferation. We show that in airway basal cells, SPRY2 is post-translationally modified in response to FGFR1 signaling. This allows SPRY2 to inhibit intracellular signaling downstream of other receptor tyrosine kinases and restrain basal cell proliferation. An FGFR1-SPRY2 signaling axis has previously been characterized in cell lines in vitro. We now demonstrate an in vivo biological function of this interaction and thus identify an active signaling mechanism that maintains quiescence in the airway epithelium.This study was supported by the Medical Research Council (G0900424 to ER); Wellcome Trust clinical PhD fellowship (JJ). Core grants: Gurdon Institute: Wellcome Trust (092096), Cancer Research UK (C6946/A14492); Stem Cell Initiative: Wellcome Trust/MRC.This is the final version of the article. It first appeared from Elsevier via https://doi.org/10.1016/j.devcel.2016.03.00

NuRD-mediated deacetylation of H3K27 facilitates recruitment of Polycomb Repressive Complex 2 to direct gene repression

The NURD and Polycomb complexes PRC1 and PRC2 have been implicated in stem cell differentiation although their molecular roles are unclear. This study identifies a common set of genes that are sequentially regulated by these complexes, the NURD complex deacetylates H3K27 as a prerequisite for subsequent methylation by PRC2