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New Approaches to Assess Mechanisms of Action of Selective Vitamin D Analogues

Recent studies of transcription have revealed an advanced set of overarching principles that govern vitamin D action on a genome-wide scale. These tenets of vitamin D transcription have emerged as a result of the application of now well-established techniques of chromatin immunoprecipitation coupled...

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Autores principales: Pike, John Wesley, Meyer, Mark B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619157/
https://www.ncbi.nlm.nih.gov/pubmed/34830234
http://dx.doi.org/10.3390/ijms222212352
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author Pike, John Wesley
Meyer, Mark B.
author_facet Pike, John Wesley
Meyer, Mark B.
author_sort Pike, John Wesley
collection PubMed
description Recent studies of transcription have revealed an advanced set of overarching principles that govern vitamin D action on a genome-wide scale. These tenets of vitamin D transcription have emerged as a result of the application of now well-established techniques of chromatin immunoprecipitation coupled to next-generation DNA sequencing that have now been linked directly to CRISPR-Cas9 genomic editing in culture cells and in mouse tissues in vivo. Accordingly, these techniques have established that the vitamin D hormone modulates sets of cell-type specific genes via an initial action that involves rapid binding of the VDR–ligand complex to multiple enhancer elements at open chromatin sites that drive the expression of individual genes. Importantly, a sequential set of downstream events follows this initial binding that results in rapid histone acetylation at these sites, the recruitment of additional histone modifiers across the gene locus, and in many cases, the appearance of H3K36me3 and RNA polymerase II across gene bodies. The measured recruitment of these factors and/or activities and their presence at specific regions in the gene locus correlate with the emerging presence of cognate transcripts, thereby highlighting sequential molecular events that occur during activation of most genes both in vitro and in vivo. These features provide a novel approach to the study of vitamin D analogs and their actions in vivo and suggest that they can be used for synthetic compound evaluation and to select for novel tissue- and gene-specific features. This may be particularly useful for ligand activation of nuclear receptors given the targeting of these factors directly to genetic sites in the nucleus.
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spelling pubmed-86191572021-11-27 New Approaches to Assess Mechanisms of Action of Selective Vitamin D Analogues Pike, John Wesley Meyer, Mark B. Int J Mol Sci Review Recent studies of transcription have revealed an advanced set of overarching principles that govern vitamin D action on a genome-wide scale. These tenets of vitamin D transcription have emerged as a result of the application of now well-established techniques of chromatin immunoprecipitation coupled to next-generation DNA sequencing that have now been linked directly to CRISPR-Cas9 genomic editing in culture cells and in mouse tissues in vivo. Accordingly, these techniques have established that the vitamin D hormone modulates sets of cell-type specific genes via an initial action that involves rapid binding of the VDR–ligand complex to multiple enhancer elements at open chromatin sites that drive the expression of individual genes. Importantly, a sequential set of downstream events follows this initial binding that results in rapid histone acetylation at these sites, the recruitment of additional histone modifiers across the gene locus, and in many cases, the appearance of H3K36me3 and RNA polymerase II across gene bodies. The measured recruitment of these factors and/or activities and their presence at specific regions in the gene locus correlate with the emerging presence of cognate transcripts, thereby highlighting sequential molecular events that occur during activation of most genes both in vitro and in vivo. These features provide a novel approach to the study of vitamin D analogs and their actions in vivo and suggest that they can be used for synthetic compound evaluation and to select for novel tissue- and gene-specific features. This may be particularly useful for ligand activation of nuclear receptors given the targeting of these factors directly to genetic sites in the nucleus. MDPI 2021-11-16 /pmc/articles/PMC8619157/ /pubmed/34830234 http://dx.doi.org/10.3390/ijms222212352 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Pike, John Wesley
Meyer, Mark B.
New Approaches to Assess Mechanisms of Action of Selective Vitamin D Analogues
title New Approaches to Assess Mechanisms of Action of Selective Vitamin D Analogues
title_full New Approaches to Assess Mechanisms of Action of Selective Vitamin D Analogues
title_fullStr New Approaches to Assess Mechanisms of Action of Selective Vitamin D Analogues
title_full_unstemmed New Approaches to Assess Mechanisms of Action of Selective Vitamin D Analogues
title_short New Approaches to Assess Mechanisms of Action of Selective Vitamin D Analogues
title_sort new approaches to assess mechanisms of action of selective vitamin d analogues
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619157/
https://www.ncbi.nlm.nih.gov/pubmed/34830234
http://dx.doi.org/10.3390/ijms222212352
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