Biology subjects

Narita, T.

Publications and source records attributed to Narita, T..

3 recordsLinked to original sources

bioRxiv2022

The logic of native enhancer-promoter compatibility and cell-type-specific gene expression variation

Cis-regulatory enhancers are essential for differential expression of developmental and housekeeping genes. However, the specificity of native mammalian enhancers and how it shapes cell-type-specific gene expression landscapes remain largely unknown. We show that endogenous enhancers are broadly compatible with the promoters of developmental and housekeeping genes. Broad enhancer compatibility affords retrofitting new regulatory capabilities to housekeeping genes that evolved before the advent of enhancers. This enables cell-type-specific tuning of ubiquitously expressed genes. Segregation between enhancer-dependent and -independent type regulation is blurred. Within the same cell type, a single promoter can be activated by enhancers and non-enhancer promoter-regulatory elements (PREs). It is the tunable and integrated strengths of enhancers and PREs that quantitatively shape gene expression landscapes, within and across cell types. Our findings have broad implications for understanding cell-type-specific quantitative gene expression variation, as well as the emergence and rewiring of gene regulatory networks in disease and organismal evolution.

genomics↗

bioRxiv2022

A unique H2B acetylation signature marks active enhancers and predicts their target genes

Chromatin features are widely used for genome-scale mapping of enhancers. However, discriminating active enhancers from other cis-regulatory elements, predicting enhancer strength, and identifying their target genes remains challenging. Here we establish histone H2B N-terminus multisite lysine acetylation (H2BNTac) as a genuine signature of active enhancers. H2BNTac prominently marks candidate active enhancers and their target promoters and discriminates them from ubiquitously active promoters. Two mechanisms afford the distinct H2BNTac specificity. (1) Unlike H3K27ac, H2BNTac is specifically catalyzed by CBP/p300. (2) H2A-H2B, but not H3-H4, are rapidly exchanged through transcription-induced nucleosome remodeling. H2BNTac-positive candidate enhancers show a high validation rate in orthogonal enhancer activity assays, and a vast majority of endogenously active enhancers are marked by H2BNTac and H3K27ac. Notably, H2BNTac intensity predicts enhancer strength and outperforms the current state-of-the-art models in predicting enhancer target genes. These findings have broad implications for generating fine-grained enhancer maps and modeling enhancer-dependent gene regulation.

genomics↗

bioRxiv2021

Myosin phosphatase target subunit 1 governs integrity of the embryonic gut epithelium to circumvent atresia development in medaka, Oryzias latipes

Congenital intestinal atresia (IA) is a birth defect characterised by the absence or closure of part of the intestine. Although genetic factors are implicated, mechanistic understanding has been hindered by the lack of suitable animal models. Here, we describe a medaka (Oryzias latipes) mutant, generated by N-ethyl-N-nitrosourea (ENU) mutagenesis, that develops IA during embryogenesis. Positional cloning identified a nonsense mutation in mypt1, encoding myosin phosphatase target subunit 1. Mutant embryos exhibited ectopic accumulation of F-actin and phosphorylated myosin regulatory light chain (Mrlc) in the intestinal epithelium, consistent with disrupted actomyosin regulation. These cytoskeletal abnormalities were accompanied by epithelial disorganisation without notable alterations in cell proliferation, motility, or apoptosis. Inhibition of myh11a, encoding smooth muscle (SM) myosin heavy chain, ameliorated the IA phenotype but Blebbistatin treatment completely rescued the defect, suggesting a non-contractile role prior to SM maturation. Together, these findings demonstrate that mypt1 loss disrupts intestinal morphogenesis through actomyosin dysregulation. Given the recent clinical identification of IA associated with MYPT1 mutations, this medaka model offers a valuable platform to investigate the developmental and molecular basis of MYPT1-associated IA in human.

developmental biology↗