RESUMEN
Genetic variants associated with type 2 diabetes (T2D) risk affect gene regulation in metabolically relevant tissues, such as pancreatic islets. Here, we investigated contributions of regulatory programs active during pancreatic development to T2D risk. Generation of chromatin maps from developmental precursors throughout pancreatic differentiation of human embryonic stem cells (hESCs) identifies enrichment of T2D variants in pancreatic progenitor-specific stretch enhancers that are not active in islets. Genes associated with progenitor-specific stretch enhancers are predicted to regulate developmental processes, most notably tissue morphogenesis. Through gene editing in hESCs, we demonstrate that progenitor-specific enhancers harboring T2D-associated variants regulate cell polarity genes LAMA1 and CRB2. Knockdown of lama1 or crb2 in zebrafish embryos causes a defect in pancreas morphogenesis and impairs islet cell development. Together, our findings reveal that a subset of T2D risk variants specifically affects pancreatic developmental programs, suggesting that dysregulation of developmental processes can predispose to T2D.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Epigenoma , Péptidos y Proteínas de Señalización Intracelular/genética , Factores de Transcripción/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Animales , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Factores de Transcripción/metabolismo , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismoRESUMEN
FOXA pioneer transcription factors (TFs) associate with primed enhancers in endodermal organ precursors. Using a human stem cell model of pancreas differentiation, we here discover that only a subset of pancreatic enhancers is FOXA-primed, whereas the majority is unprimed and engages FOXA upon lineage induction. Primed enhancers are enriched for signal-dependent TF motifs and harbor abundant and strong FOXA motifs. Unprimed enhancers harbor fewer, more degenerate FOXA motifs, and FOXA recruitment to unprimed but not primed enhancers requires pancreatic TFs. Strengthening FOXA motifs at an unprimed enhancer near NKX6.1 renders FOXA recruitment pancreatic TF-independent, induces priming, and broadens the NKX6.1 expression domain. We make analogous observations about FOXA binding during hepatic and lung development. Our findings suggest a dual role for FOXA in endodermal organ development: first, FOXA facilitates signal-dependent lineage initiation via enhancer priming, and second, FOXA enforces organ cell type-specific gene expression via indirect recruitment by lineage-specific TFs.
Asunto(s)
Endodermo/embriología , Elementos de Facilitación Genéticos/genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Factor Nuclear 3-beta del Hepatocito/metabolismo , Sitios de Unión , Diferenciación Celular , Células Madre Embrionarias/citología , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/genética , Humanos , Hígado/embriología , Pulmón/embriología , Motivos de Nucleótidos , Especificidad de Órganos , Organogénesis , Páncreas/embriología , Transactivadores/genéticaRESUMEN
The nuclear lamina (NL) is a thin meshwork of filaments that lines the inner nuclear membrane, thereby providing a platform for chromatin binding and supporting genome organization. Genomic regions contacting the NL are lamina associated domains (LADs), which contain thousands of genes that are lowly transcribed, and enriched for repressive histone modifications. LADs are dynamic structures that shift spatial positioning in accordance with cell-type specific gene expression changes during differentiation and development. Furthermore, recent studies have linked the disruption of LADs and alterations in the epigenome with the onset of diseases such as cancer. Here we focus on the role of LADs and the NL in gene regulation during development and cancer.