Gene silencing dynamics are modulated by transiently active regulatory elements.

Vermunt MW., Luan J., Zhang Z., Thrasher AJ., Huang A., Saari MS., Khandros E., Beagrie RA., Zhang S., Vemulamada P., Brilleman M., Lee K., Yano JA., Giardine BM., Keller CA., Hardison RC., Blobel GA.

Transcriptional enhancers have been extensively characterized, but cis-regulatory elements involved in acute gene repression have received less attention. Transcription factor GATA1 promotes erythroid differentiation by activating and repressing distinct gene sets. Here, we study the mechanism by which GATA1 silences the proliferative gene Kit during murine erythroid cell maturation and define stages from initial loss of activation to heterochromatinization. We find that GATA1 inactivates a potent upstream enhancer but concomitantly creates a discrete intronic regulatory region marked by H3K27ac, short noncoding RNAs, and de novo chromatin looping. This enhancer-like element forms transiently and serves to delay Kit silencing. The element is ultimately erased via the FOG1/NuRD deacetylase complex, as revealed by the study of a disease-associated GATA1 variant. Hence, regulatory sites can be self-limiting by dynamic co-factor usage. Genome-wide analyses across cell types and species uncover transiently active elements at numerous genes during repression, suggesting that modulation of silencing kinetics is widespread.

DOI

10.1016/j.molcel.2023.02.006

Type

Journal article

Journal

Molecular cell

Publication Date

03/2023

Volume

83

Pages

715 - 730.e6

Addresses

Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: vermuntm@chop.edu.

Keywords

Animals, Mice, Cell Differentiation, Gene Silencing, Regulatory Sequences, Nucleic Acid, Introns, Genome-Wide Association Study, Mi-2 Nucleosome Remodeling and Deacetylase Complex

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