Genome‐Wide Maps of Transcription Regulatory Elements and Transcription Enhancers in Development and Disease

Agrawal, Puja; Heimbruch, Katelyn E.; Rao, Sridhar

doi:10.1002/cphy.c180028

Cited by 14 publications

(13 citation statements)

References 125 publications

(164 reference statements)

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“…The advent of chromosome capture technologies has allowed the identification of more interactions between chromosomal regions than ever before (reviewed by Agrawal et al 15 ). A new field emerged through the rise of these techniques: nuclear architecture, the 3-dimensional organization of chromatin within nuclear space ( Fig.…”

Section: The Cohesin Complexmentioning

confidence: 99%

A cohesive look at leukemogenesis: The cohesin complex and other driving mutations in AML

et al. 2021

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Acute myeloid leukemia (AML) affects tens of thousands of patients a year, yet survival rates are as low as 25% in certain populations. This poor survival rate is partially due to the vast genetic diversity of the disease. Rarely do 2 patients with AML have the same mutational profile, which makes the development of targeted therapies particularly challenging. However, a set of recurrent mutations in chromatin modifiers have been identified in many patients, including mutations in the cohesin complex, which have been identified in up to 20% of cases. Interestingly, the canonical function of the cohesin complex in establishing sister chromatid cohesin during mitosis is unlikely to be the affected role in leukemogenesis. Instead, the cohesin complex's role in DNA looping and gene regulation likely facilitates disease. The epigenetic mechanisms by which cohesin complex mutations promote leukemia are not completely elucidated, but alterations of enhancer-promoter interactions and differential histone modifications have been shown to drive oncogenic gene expression changes. Such changes commonly include HoxA upregulation, which may represent a common pathway that could be therapeutically targeted. As cohesin mutations rarely occur alone, examining the impact of common co-occurring mutations, including those in NPM1, the core-binding factor complex, FLT3, and ASXL1, will yield additional insight. While further study of these mutational interactions is required, current research suggests that the use of combinatorial genetics could be the key to uncovering new targets, allowing for the treatment of AML patients based on their individual genetic profiles.

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Section: The Cohesin Complexmentioning

confidence: 99%

A cohesive look at leukemogenesis: The cohesin complex and other driving mutations in AML

et al. 2021

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“…The RegSNP program also suggested that the ECR1(T) allele would bind the CTCF transcription factor with higher affinity. This is intriguing as CTCF is a known marker for the function of regulatory sequences known as insulators that protect promoters against the effects of enhancer sequences (Agrawal, Heimbruch, & Rao, ).…”

Section: Resultsmentioning

confidence: 99%

Disease‐associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue‐specific activity of the cannabinoid‐1 receptor gene promoter; implications for cannabinoid pharmacogenetics

et al. 2019

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Cannabinoid receptor-1 (CB1) represents a potential drug target against conditions that include obesity and substance abuse. However, drug trials targeting CB1 (encoded by the CNR1 gene) have been compromised by differences in patient response. Toward addressing the hypothesis that genetic changes within the regulatory regions controlling CNR1 expression contribute to these differences, we characterized the effects of disease-associated allelic variation within a conserved regulatory sequence (ECR1) in CNR1 intron 2 that had previously been shown to modulate cannabinoid response, alcohol intake, and anxiety-like behavior. We used primary cell analysis of reporters carrying different allelic variants of the human ECR1 and found that humanspecific C-allele variants of ECR1 (ECR1(C)) drove higher levels of CNR1prom activity in primary hippocampal cells than did the ancestral T-allele and demonstrated a differential response to CB1 agonism. We further demonstrate a role for the AP-1 transcription factor in driving higher ECR1(C) activity and evidence that the ancestral tallele variant of ECR1 interacted with higher affinity with the insulator binding factor CTCF. The cell-specific approaches used in our study represent an important step in gaining a mechanistic understanding of the roles of noncoding polymorphic variation in disease and in the increasingly important field of cannabinoid pharmacogenetics. K E Y W O R D S212-2, AP-1, cannabinoid pharmacogenetics, CB1 agonists, chromatin immunoprecipitation,

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“…Enhancers are CREs that contain DNA-binding motifs for transcription factors (TFs) distal to the gene promoter, which are located immediately adjacent to the transcriptional start site (TSS). Binding of these TFs drives enhancers to promote or repress gene expression through multiple mechanisms that are beyond the scope of this review ( Li et al, 2016 ; Chen et al, 2018 ; Agrawal et al, 2019 ). Next-generation sequencing-based (NGS) methods have revolutionized the genome-wide identification of enhancers.…”

Section: Enhancersmentioning

confidence: 99%

“…For further information on enhancer and CTCF functions, we suggest these reviews (Ong and Corces, 2014;Shlyueva et al, 2014;Li et al, 2016;Chen et al, 2018;Rowley and Corces, 2018;Agrawal et al, 2019;Braccioli and De Wit, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…The examples discussed below do not encompass all the literature available by any measure but reflect selected key studies in the field focusing on embryonic stem cells (ESCs). For further information on enhancer and CTCF functions, we suggest these reviews ( Ong and Corces, 2014 ; Shlyueva et al, 2014 ; Li et al, 2016 ; Chen et al, 2018 ; Rowley and Corces, 2018 ; Agrawal et al, 2019 ; Braccioli and De Wit, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Super-Enhancers and CTCF in Early Embryonic Cell Fate Decisions

Agrawal

Rao

2021

Front. Cell Dev. Biol.

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Cell fate decisions are the backbone of many developmental and disease processes. In early mammalian development, precise gene expression changes underly the rapid division of a single cell that leads to the embryo and are critically dependent on autonomous cell changes in gene expression. To understand how these lineage specifications events are mediated, scientists have had to look past protein coding genes to the cis regulatory elements (CREs), including enhancers and insulators, that modulate gene expression. One class of enhancers, termed super-enhancers, is highly active and cell-type specific, implying their critical role in modulating cell-type specific gene expression. Deletion or mutations within these CREs adversely affect gene expression and development and can cause disease. In this mini-review we discuss recent studies describing the potential roles of two CREs, enhancers and binding sites for CTCF, in early mammalian development.

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Genome‐Wide Maps of Transcription Regulatory Elements and Transcription Enhancers in Development and Disease

Cited by 14 publications

References 125 publications

A cohesive look at leukemogenesis: The cohesin complex and other driving mutations in AML

A cohesive look at leukemogenesis: The cohesin complex and other driving mutations in AML

Disease‐associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue‐specific activity of the cannabinoid‐1 receptor gene promoter; implications for cannabinoid pharmacogenetics

Super-Enhancers and CTCF in Early Embryonic Cell Fate Decisions

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