Druley, T. E. | Search bioRxiv

bioRxiv2021

KDM6A knockout in human iPSCs alters the genome-wide histone methylation profile at active and poised enhancers, activating expression of ectoderm gene expression pathways.

KDM6A is a histone demethylase, known to remove methyl moieties at the lysine residues of histone 3-labeled (H3K27me3) poised enhancers and bivalent promoters, which regulates gene expression during the differentiation of embryonic stem cells and tissue-specific development. However, while tissue- and disease-specific analyses have been performed, little is known about the location and consequences on gene expression of these regulatory regions in human pluripotent cells. Poised enhancers and bivalent promoters function in a coordinated fashion during development, which requires timely and efficient histone modifications. Identification of KDM6A-specific gene-regulatory domains is important for understanding the developmental mechanisms controlled by these histone modifications in pluripotency. In this study, we compared genome-wide histone modification and gene expression differences in isogenic wild type and cas9-mediated KDM6A knockout human induced pluripotent stem cells (hiPSC) lines. Here, we report that the absence of KDM6A does not alter the pluripotent phenotype but does substantially alter the histone modification profile at poised and active enhancers, resulting in decreased expression of associated COMPASS complex genes KMT2C and KMT2D and subsequently increasing the expression of gene pathways involved in ectoderm differentiation.

genomics↗

bioRxiv2019

The Evolutionary Dynamics and Fitness Landscape of Clonal Haematopoiesis

Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance, however, remains largely unknown. Here, by combining blood sequencing data from [~]50,000 individuals, we reveal how mutation, genetic drift and fitness differences combine to shape the genetic diversity of healthy blood ( clonal haematopoiesis). By analysing the spectrum of variant allele frequencies we quantify fitness advantages for key pathogenic variants and genes and provide bounds on the number of haematopoietic stem cells. Positive selection, not drift, is the major force shaping clonal haematopoiesis. The remarkably wide variation in variant allele frequencies observed across individuals is driven by chance differences in the timing of mutation acquisition combined with differences in the cell-intrinsic fitness effect of variants. Contrary to the widely held view that clonal haematopoiesis is driven by ageing-related alterations in the stem cell niche, the data are consistent with the age dependence being driven simply by continuing risk of mutations and subsequent clonal expansions that lead to increased detectability at older ages.

genomics↗