TY - JOUR
T1 - Contribution of CTCF binding to transcriptional activity at the HOXA locus in NPM1-mutant AML cells
AU - Ghasemi, Reza
AU - Struthers, Heidi
AU - Wilson, Elisabeth R.
AU - Spencer, David H.
N1 - Funding Information:
Acknowledgements This work was supported by the American Society of Hematology (ASH Scholar Award), the American Cancer Society (Institutional Research Grant), and the National Cancer Institute (K08CA190815, SPORE Career Enhancement Award, P50 CA171963, D. Link, PI) to DHS. Primary AML samples were provided by the Genomics of AML Program Project (P01CA101937, T. Ley, PI). Technical assistance was provided by the Siteman Cancer Center Tissue Procurement and Cell Sorting cores (NCI Cancer Center Support Grant P30CA91842).
Publisher Copyright:
© 2020, The Author(s).
PY - 2021/2
Y1 - 2021/2
N2 - Transcriptional regulation of the HOXA genes is thought to involve CTCF-mediated chromatin loops and the opposing actions of the COMPASS and Polycomb epigenetic complexes. We investigated the role of these mechanisms at the HOXA cluster in AML cells with the common NPM1c mutation, which express both HOXA and HOXB genes. CTCF binding at the HOXA locus is conserved across primary AML samples, regardless of HOXA gene expression, and defines a continuous chromatin domain marked by COMPASS-associated histone H3 trimethylation in NPM1-mutant primary AML samples. Profiling of the three-dimensional chromatin architecture in primary AML samples with the NPM1c mutation identified chromatin loops between the HOXA cluster and loci in the SNX10 and SKAP2 genes, and an intergenic region located 1.4 Mbp upstream of the HOXA locus. Deletion of CTCF binding sites in the NPM1-mutant OCI-AML3 AML cell line reduced multiple long-range interactions, but resulted in CTCF-independent loops with sequences in SKAP2 that were marked by enhancer-associated histone modifications in primary AML samples. HOXA gene expression was maintained in CTCF binding site mutants, indicating that transcriptional activity at the HOXA locus in NPM1-mutant AML cells may be sustained through persistent interactions with SKAP2 enhancers, or by intrinsic factors within the HOXA gene cluster.
AB - Transcriptional regulation of the HOXA genes is thought to involve CTCF-mediated chromatin loops and the opposing actions of the COMPASS and Polycomb epigenetic complexes. We investigated the role of these mechanisms at the HOXA cluster in AML cells with the common NPM1c mutation, which express both HOXA and HOXB genes. CTCF binding at the HOXA locus is conserved across primary AML samples, regardless of HOXA gene expression, and defines a continuous chromatin domain marked by COMPASS-associated histone H3 trimethylation in NPM1-mutant primary AML samples. Profiling of the three-dimensional chromatin architecture in primary AML samples with the NPM1c mutation identified chromatin loops between the HOXA cluster and loci in the SNX10 and SKAP2 genes, and an intergenic region located 1.4 Mbp upstream of the HOXA locus. Deletion of CTCF binding sites in the NPM1-mutant OCI-AML3 AML cell line reduced multiple long-range interactions, but resulted in CTCF-independent loops with sequences in SKAP2 that were marked by enhancer-associated histone modifications in primary AML samples. HOXA gene expression was maintained in CTCF binding site mutants, indicating that transcriptional activity at the HOXA locus in NPM1-mutant AML cells may be sustained through persistent interactions with SKAP2 enhancers, or by intrinsic factors within the HOXA gene cluster.
UR - http://www.scopus.com/inward/record.url?scp=85084511977&partnerID=8YFLogxK
U2 - 10.1038/s41375-020-0856-3
DO - 10.1038/s41375-020-0856-3
M3 - Article
C2 - 32398790
AN - SCOPUS:85084511977
VL - 35
SP - 404
EP - 416
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 2
ER -