Please use this identifier to cite or link to this item:
http://bura.brunel.ac.uk/handle/2438/20318
Title: | Loss of Kat2A Enhances Transcriptional Noise and Depletes Acute Myeloid Leukemia Stem-Like Cells |
Authors: | Domingues, AF Kulkarni, R Giotopoulos, G Gupta, S Tan, S Foerner, E Adao, RR Zeka, K Huntly, BJ Prabakaran, S Pina, C |
Issue Date: | 2018 |
Publisher: | Cold Spring Harbor Laboratory |
Citation: | bioRxiv, 2018 446096 |
Abstract: | Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective myelo-monocytic differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutation and by hijacking normal chromatin regulation. Kat2a is a histone acetyltransferase central to promoter activity that we recently associated with stability of pluripotency networks, and identified as a genetic vulnerability in AML. Through combined chromatin profiling and single-cell transcriptomics, we demonstrate that Kat2a contributes to leukemia propagation through homogeneity of transcriptional programs and preservation of leukemia stem-like cells. Kat2a loss reduces transcriptional bursting frequency in a subset of gene promoters, generating enhanced variability of transcript levels but minimal effects on mean gene expression. Destabilization of target programs shifts cellular equilibrium out of self-renewal towards differentiation. We propose that control of transcriptional variability is central to leukemia stem-like cell propagation, and establish a paradigm exploitable in different tumors and at distinct stages of cancer evolution. |
URI: | https://bura.brunel.ac.uk/handle/2438/20318 |
DOI: | https://doi.org/10.1101/446096 |
Appears in Collections: | Dept of Life Sciences Research Papers |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
FullText.pdf | 5.49 MB | Adobe PDF | View/Open |
Items in BURA are protected by copyright, with all rights reserved, unless otherwise indicated.