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Clustering analysis linking the activities of stage-specific transcriptional enhancers with gene expression during blood cell development

This publication from the Bonifer laboratory describes a novel genome-wide screen that identified and functionally characterised distinct subsets of gene regulatory elements that direct the different stages of the development of blood cells from embryonic stem cells (ESC)

Nature Communications 14:267 (2023). Edginton-White B, A Maytum, SG Kellaway, DK Goode, P Keane,. . . C Bonifer. A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification. doi: 10.1038/s41467-023-35910-9

This study of the genome investigated the functions of all of the regulatory elements within our DNA that are required to express our genes in the right cells, at the right levels, and at the right time.

These regulatory elements are called enhancers and are scattered over large distances within the the 3 billion bases of DNA that make up the geneome. Enhancers also function to integrate multiple highly specific intrinsic and extrinsic signals, whereby most regulatory elements only function in a subset of cells. The Bonifer laboratory developed a whole genome assay able to define the precise time course of activation of enhancers, and their responses to external signals, during the stepwise development of blood cells from ESCs.

These analyses identified thousands of differentially active enhancers able to stimulate a promoter across different stages of blood cell development from ESCs. It also showed that blood cell-specific gene expression is controlled by the concerted action of thousands of differentiation stage-specific sets of enhancers and promoters, many of which respond to the cytokine signals promoting cell differentiation towards blood cells. This work highlights the mechanisms of how and where extrinsic signals program a cell type-specific regulatory landscape driving hematopoietic differentiation.