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Our long-term goal is to provide insight into the molecular mechanisms responsible for the coordinated development of complex organ systems, which has relevance to human congenital birth defects, and cryptic susceptibilities to disease or syndromes. The vertebrate body is built by a series of progressively refined decisions. First, long-range decisions have to be made on how the “head to tail” axis is formed. Then, specific tissue territories must acquire the potential to form each organ (brain, spinal cord, lungs, liver, gut, pancreas) in the right place at the right time. They must all become hooked up to each other properly, attached to the blood supply, and also become innervated. The transcription-factor–based (TF-based) and epigenetically guided gene-regulatory networks controlling these decisions can be dissected by various methods. A predominant view is that chromatin is progressively opened up from a closed state, to allow access to genes and their cis-reguatory regions. For example, enhancers may be released from heterochromatin by the ability of pioneer TFs to crack open the condensed chromatin state. Thereafter, regulatory cofactors are recruited to those accessible chromatin domains. Cis-regulatory DNA regions, or enhancers, can be differentially marked by post-translational modifications (PTMs) of their histones and other chromatin proteins. They are initially marked equivalently by PTMs that are repressive or activating with respect to the transcriptional state of the locus, causing a so-called “bivalent” condition. Addition or removal of the marking leads to predominance in one or the other type of marking, to close down or allow transcription to occur. These processes operate in carefully orchestrated tiers of action. Genes allowed to activate, through the action of the first-arriving pioneer TFs, can produce other TFs or regulatory proteins. These proteins are themselves then able to search the genome and land on other chromosome locations to cause activation or repression of (small or large) sets of target genes. Combinatorial action with the pioneer factors is often encountered.
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Angelica S. Martinez-Ramirez, Thomas L. Borders,Leena Paul,Matthew Schipma,Xinkun Wang, Farida Korobova,Christopher V. Wright,Beatriz Sosa-Pineda
Gastro Hep Advancesno. 5 (2022): 807-823
Jason M Spaeth,Jin-Hua Liu, Daniel Peters,Min Guo,Anna B Osipovich, Fardin Mohammadi,Nilotpal Roy,Anil Bhushan,Mark A Magnuson,Matthias Hebrok,Christopher V E Wright,Roland Stein
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