The linker histone H1 organizes nucleosomes into higher-order structures, increasing chromatin folding, and is associated with decreased transcription 3, 4. Relatively less is known about how nonhistone nucleosome-associated proteins that modify chromatin compaction and accessibility contribute to transformation.Д¬hromatin accessibility affects gene expression by altering interactions of transcriptional regulatory factors with their targets. Cancer cells frequently acquire abnormalities in the same chromatin regulatory pathways, which promote malignancy and may impart targetable therapeutic dependencies 2. Chromatin regulation by chemical modification of DNA or histones modulates gene expression and is important for development, differentiation, and response to signals 1. In eukaryotic cells, DNA is packaged into chromatin, a dynamic structure containing genomic DNA, histones, and nonhistone proteins. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs, and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block. HMGN1 overexpression also cooperates with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. In vivo, HMGN1 overexpression is linked to decreased quiescence and increased HSC activity in bone marrow transplantation.

HMGN1 amplification is associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cells (HSCs) and leukemia, such as HoxA cluster genes.

Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes.

Graphpad prism 8 accessibility