Abstract
Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. 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. In vivo, HMGN1 overexpression is linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperates with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block. 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.
Highlights
Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes
This is consistent with data from other tissues where downregulation of HMGN1 is linked with differentiation to specific lineages[18]
Hmgn[1] is located on chromosome 16 and is trisomic in several models of Down syndrome, including Ts1Rhr[22], which triplicates 31 genes orthologous to a segment of human chr21q22 that is recurrently amplified in acute myeloid leukemia (AML)
Summary
Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. 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. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block 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. HMGN genomic positioning is not random; it preferentially co-localizes with regulatory marks at active promoters and affects nucleosome organization, DNase hypersensitivity patterns, and posttranslational histone marks[8,9] Despite these links between HMGNs and chromatin regulation, a mechanistic understanding of how HMGNs contribute to disease is not as well understood. How 21q22/HMGN1 amplification affects HSPCs/myeloid differentiation or confers therapeutic vulnerability is not clear
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