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Comprehensive epigenomic profiling of human alveolar epithelial differentiation identifies key epigenetic states and transcription factor co-regulatory networks for maintenance of distal lung identity

ABSTRACT: Background: Disruption of alveolar epithelial cell (AEC) differentiation is implicated in implicated in distal lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung adenocarcinoma that impact morbidity and mortality worldwide. Elucidating underlying disease pathogenesis requires a mechanistic molecular understanding of AEC differentiation. Previous studies have focused on changes of individual transcription factors, and to date no study has comprehensively characterized the dynamic, global epigenomic alterations that facilitate this critical differentiation process in humans. We comprehensively profiled the epigenomic states of human AECs during type 2 to type 1-like cell differentiation, including the methylome and chromatin functional domains, and integrated this with transcriptome-wide RNA expression data. Enhancer regions were drastically altered during AEC differentiation. Transcription factor binding analysis within enhancer regions revealed diverse interactive networks with enrichment for many transcription factors, including NKX2-1 and FOXA family members, as well as transcription factors with less well characterized roles in AEC differentiation, such as members of the MEF2, TEAD, and AP1 families. Additionally, associations among transcription factors changed during differentiation, implicating a complex network of heterotrimeric complex switching in driving differentiation. Integration of AEC enhancer states with the catalog of enhancer elements in the Roadmap Epigenomics Mapping Consortium and Encyclopedia of DNA Elements (ENCODE) revealed that AECs have similar epigenomic structures to other profiled epithelial cell types, including human mammary epithelial cells (HMECs), with NKX2-1 serving as a distinguishing feature of distal lung differentiation. Enhancer regions are hotspots of epigenomic alteration that regulate AEC differentiation. Furthermore, the differentiation process is regulated by dynamic networks of transcription factors acting in concert, rather than individually. These findings provide a roadmap for understanding the relationship between disruption of the epigenetic state during AEC differentiation and development of lung diseases that may be therapeutically amenable.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150527 | GEO | 2021/10/27

REPOSITORIES: GEO

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Project description:Lung adenocarcinoma (LUAD) is the predominant lung cancer subtype. To date, 15 single nucleotide polymorphisms (SNPs) have been reproducibly associated with LUAD susceptibility. However, as most SNPs identified in genome-wide association studies (GWAS) are not located in the coding regions of genes and are co-inherited with hundreds of SNPs in linkage disequilibrium (LD), mechanistic links to disease outcomes remain largely unexplored. We hypothesized that some SNPs increase LUAD risk by affecting enhancers of gene transcription in alveolar epithelial cells (AECs), the purported cells of origin for LUAD. Forty-six LUAD risk-associated SNPs mapped to putative AEC enhancers, and 11 of these were located in FAIRE peaks. Of those, seven were predicted to form transcription factor binding motifs. For four of these, ChIPseq data confirmed the binding of the predicted transcription factors. We chose rs452384, rs6942067 and rs11364096 for functional validation. The reference (risk) allele for rs452384 forms an NKX2-1 binding site that is disrupted by the alternate allele, elicited a 42% increase in activity in H1648 LUAD cells relative to the alternative allele (P = 6.7 x 10-3), and was associated with elevated TERT levels in esophageal tissue (P = 6 x 10-8). The reference (risk) allele for rs6942067 forms an EP300 binding site disrupted by the alternate allele, elicits a 94% increase in enhancer activity relative to the alternative allele in H1648 LUAD cells (P = 2.7 x 10-2), and was associated with higher expression of potential oncogene DCBLD1 in blood (P = 5.2 x 10-16). Lastly, the alternate (risk) allele for rs11364096 disrupts binding sites for FOXA1, HDAC2 and SP1, elicits a 32% decrease in enhancer activity in A549 LUAD cells relative to the reference allele (P = 5.7 x 10-3), and LUAD data from The Cancer Genome Atlas indicates that this SNP is associated with altered expression in LUAD of four genes on other chromosomes. Our analyses provide possible mechanisms for the genetic susceptibility to LUAD, with the identification of three strong functional SNP candidates that appear to affect AEC enhancers. Further investigation of these enhancers and their target genes may ultimately yield more effective and personalized strategies for LUAD risk assessment, prevention and treatment.

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Comprehensive epigenomic profiling of human alveolar epithelial differentiation identifies key epigenetic states and transcription factor co-regulatory networks for maintenance of distal lung identity

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