ESPEYB19 1. Pituitary and Neuroendocrinology Basic Science and Stem Cells (4 abstracts)
1.2. Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits
Pahl MC , Doege CA , Hodge KM , Littleton SH , Leonard ME , Lu S , Rausch R , Pippin JA , De Rosa MC , Basak A , Bradfield JP , Hammond RK , Boehm K , Berkowitz RI , Lasconi C , Su C , Chesi A , Johnson ME , Wells AD , Voight BF , Leibel RL , Cousminer DL & Grant SFA
Nat Commun. 2021 Nov 19;12(1):6749. doi: 10.1038/s41467-021-27001-4. PMID: 34799566.
Brief Summary: The authors used RNA-seq, ATAC-seq, and promoter-focused Capture C to characterize the genetic architecture during hypothalamic differentiation. This information provides insights into mechanisms by which noncoding GWAS loci are associated with hypothalamic-regulated traits potentially mediating their effects.
The hypothalamus controls numerous complex traits, such as timing of sexual maturation and body weight. Understanding of the traits and related diseases could be increased by studying the genetic regulation of the developing and mature human hypothalamus. However, availability of human hypothalamic tissue is limited. Moreover, in genome-wide association studies (GWAS), most signals associated with complex traits lie in the non-coding regions of the genome, indicating that they can be in cis -acting regulatory elements of gene (for instance, enhancers or silencers). Since cis -acting regulatory elements can act locally or over large distances, the closest gene to a GWAS signal may not be the main effector gene.
This study generates a high-resolution chromatin architecture atlas of an established embryonic stem cell -derived hypothalamic-like neuron model across three stages of in vitro differentiation. The authors profile open chromatin and identify physical contacts between gene promoters and putative cis -regulatory elements in order to characterize the global regulatory landscape changes during hypothalamic differentiation. The data were integrated with GWAS signals for complex traits, including body mass index, adult height, sleep, age at menarche, and psychiatric disorders. This approach pinpointed both known and novel effector genes along with their corresponding putative regulatory elements for the traits. A further biological function analysis revealed the association of the potential effector genes with central pathways for hypothalamic development.
Although a cell model is not fully comparable to in vivo conditions, this paper provides valuable data for prioritizing the candidate genes that drive the hypothalamic molecular mechanisms influencing the pathogenesis of complex traits.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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