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Integrative high-throughput enhancer surveying and functional verifying divulges YY2 condensed regulatory axis conferring risk for osteoporosis

ABSTRACT: The precise roles of chromatin organizations at osteoporosis risk loci remains largely elusive. Here we combined chromatin interaction conformation (Hi-C) profiling and self-transcribing active regulatory region sequencing (STARR-seq) to qualify enhancer activities of prioritized osteoporosis-associated SNPs. We identified 319 SNPs with biased allelic enhancer activity effect (baaSNPs) which linked to hundreds of candidate target genes through chromatin interactions across 146 loci. Functional characterizations revealed active epigenetic enrichment for baaSNPs, and prevailing osteoporosis-relevant regulatory roles for their chromatin interacted genes. Further motif enrichment and network mapping prioritized several putative key transcription factors (TFs) controlling osteoporosis binding to baaSNPs. Specifically, we selected on top ranked TF and deciphered that an intronic baaSNP (rs11202530) could allele-preferentially bind to YY2 to augment PAPSS2 expression through chromatin interactions and promote osteoblast differentiation. Our results underlined roles of TF-mediated enhancer-promoter contacts for osteoporosis, which may help better understand the intricate molecular regulatory mechanisms underlying osteoporosis-risk loci.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231932 | GEO | 2023/12/29

REPOSITORIES: GEO

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Project description:Development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human hematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains nucleoporin’s IDR, tandemly dispersed phenylalanine-andglycine (FG) repeats1-3. However, it remains largely elusive how unstructured IDRs contribute to oncogenesis. We here show that IDR or FG repeats harbored within NUP98-HOXA9, a homeodomain-containing transcription factor (TF) chimera recurrently detected in acute leukemia patients1,4,5, is essential for establishing nuclear liquid-liquid phase separation (LLPS) puncta and for inducing leukemic transformation of primary hematopoietic cells in vitro and in vivo. Strikingly, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera TF oncoproteins but is also required for formation of a broad, ‘super-enhancer’-like binding pattern, typically seen at a battery of leukemia-related loci exemplified by HOX, MEIS and PBX genes, potentiating their transcriptional activation. An artificial HOX chimera, created by replacing NUP98’s FG repeats with an unrelated LLPSforming IDR of FUS6,7, had similar enhancement effects on chimera’s chromatin binding and target gene activation. Via Hi-C mapping, we further demonstrated that the phase-separated NUP98-HOXA9 protein assembly is able to induce formation of CTCF-independent chromatin looping enriched at leukemic oncogenes. Together, this report describes a proof-of-principle example wherein cancer acquires mutation to establish condensates of oncogenic TFs via a phase separation mechanism, which simultaneously enhances their chromatin targeting and induces organization of aberrant three-dimensional chromatin structure during tumorous transformation. As a range of LLPS-competent molecules are implicated in various human cancers, this mechanism can potentially be generalized to many malignant and diseased settings.

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Integrative high-throughput enhancer surveying and functional verifying divulges YY2 condensed regulatory axis conferring risk for osteoporosis

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