TY - JOUR
T1 - Noncoding variants connect enhancer dysregulation with nuclear receptor signaling in hematopoietic malignancies
AU - Li, Kailong
AU - Zhang, Yuannyu
AU - Liu, Xin
AU - Liu, Yuxuan
AU - Gu, Zhimin
AU - Cao, Hui
AU - Dickerson, Kathryn E.
AU - Chen, Mingyi
AU - Chen, Weina
AU - Shao, Zhen
AU - Ni, Min
AU - Xu, Jian
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/5
Y1 - 2020/5
N2 - Mutations in protein-coding genes are well established as the basis for human can-cer, yet how alterations within noncoding genome, a substantial fraction of which contain cis-regulatory elements (CRE), contribute to cancer pathophysiology remains elusive. Here, we developed an integrative approach to systematically identify and characterize noncoding regulatory variants with functional consequences in human hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage–associated CREs and mutation discovery, we uncovered 1,836 recurrently mutated CREs containing leukemia-associated noncoding variants. By enhanced CRISPR/ dCas9–based CRE perturbation screening and functional analyses, we identified 218 variant-associ-ated oncogenic or tumor-suppressive CREs in human leukemia. Noncoding variants at KRAS and PER2 enhancers reside in proximity to nuclear receptor (NR) binding regions and modulate transcriptional activities in response to NR signaling in leukemia cells. NR binding sites frequently colocalize with non-coding variants across cancer types. Hence, recurrent noncoding variants connect enhancer dysregula-tion with nuclear receptor signaling in hematopoietic malignancies. SIGNIFICANCE: We describe an integrative approach to identify noncoding variants in human leukemia, and reveal cohorts of variant-associated oncogenic and tumor-suppressive cis-regulatory elements including KRAS and PER2 enhancers. Our findings support a model in which noncoding regulatory variants connect enhancer dysregulation with nuclear receptor signaling to modulate gene programs in hematopoietic malignancies.
AB - Mutations in protein-coding genes are well established as the basis for human can-cer, yet how alterations within noncoding genome, a substantial fraction of which contain cis-regulatory elements (CRE), contribute to cancer pathophysiology remains elusive. Here, we developed an integrative approach to systematically identify and characterize noncoding regulatory variants with functional consequences in human hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage–associated CREs and mutation discovery, we uncovered 1,836 recurrently mutated CREs containing leukemia-associated noncoding variants. By enhanced CRISPR/ dCas9–based CRE perturbation screening and functional analyses, we identified 218 variant-associ-ated oncogenic or tumor-suppressive CREs in human leukemia. Noncoding variants at KRAS and PER2 enhancers reside in proximity to nuclear receptor (NR) binding regions and modulate transcriptional activities in response to NR signaling in leukemia cells. NR binding sites frequently colocalize with non-coding variants across cancer types. Hence, recurrent noncoding variants connect enhancer dysregula-tion with nuclear receptor signaling in hematopoietic malignancies. SIGNIFICANCE: We describe an integrative approach to identify noncoding variants in human leukemia, and reveal cohorts of variant-associated oncogenic and tumor-suppressive cis-regulatory elements including KRAS and PER2 enhancers. Our findings support a model in which noncoding regulatory variants connect enhancer dysregulation with nuclear receptor signaling to modulate gene programs in hematopoietic malignancies.
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U2 - 10.1158/2159-8290.CD-19-1128
DO - 10.1158/2159-8290.CD-19-1128
M3 - Article
C2 - 32188707
AN - SCOPUS:85084961226
SN - 2159-8274
VL - 10
SP - 724
EP - 745
JO - Cancer discovery
JF - Cancer discovery
IS - 5
ER -