Rebalancing gene haploinsufficiency in vivo by targeting chromatin

Fulcoli, Filomena Gabriella; Franzese, Monica; Li, Xiangyang; Zhang, Zhen; Angelini, Claudia; Baldini, Antonio

doi:10.1038/ncomms11688

Cited by 70 publications

(91 citation statements)

References 39 publications

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“…For example, T-box factors including T-BET and T were shown to physically interact with RBBP5, a member of the H3K4 methyltransferase complex and to control H3K4me2 at target genes [7]. Recently, TBX1 was reported to physically interact with histone methyltransferase enzymes, including MLL3, and Tbx1 knockdown resulted in a decrease in H3K4me1 levels at a subset of TBX1 binding sites [53]. Furthermore, a physical interaction between T-BET and p300 has previously been shown [51], although unlike in our study, the authors did not show a functional requirement for T-BET in the recruitment of H3K27ac to T-BET target sites.…”

Section: Discussionmentioning

confidence: 99%

BRACHYURY directs histone acetylation to target loci during mesoderm development

et al. 2017

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T-box transcription factors play essential roles in multiple aspects of vertebrate development. Here, we show that cooperative function of BRACHYURY (T) with histone-modifying enzymes is essential for mouse embryogenesis. A single point mutation (T) results in decreased histone 3 lysine 27 acetylation (H3K27ac) at T target sites, including the locus, suggesting that T autoregulates the maintenance of its expression and functions by recruiting permissive chromatin modifications to putative enhancers during mesoderm specification. Our data indicate that T mediates H3K27ac recruitment through a physical interaction with p300. In addition, we determine that T plays a prominent role in the specification of hematopoietic and endothelial cell types. Hematopoietic and endothelial gene expression programs are disrupted in mutant embryos, leading to a defect in the differentiation of hematopoietic progenitors. We show that this role of T is mediated, at least in part, through activation of a distal enhancer.

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Section: Discussionmentioning

confidence: 99%

BRACHYURY directs histone acetylation to target loci during mesoderm development

et al. 2017

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“…Del22q11 includes the T-Box transcription factor TBX1 , and haploinsufficiency for TBX1 underlies the cardio-pharyngeal phenotype 32–34 . Recent work in mice haploinsufficient for Tbx1 delineates regulation of H3K4me1 enrichment, providing an intriguing link between TBX1 and chromatin remodeling in CHD 35 . Other CHD-associated CNVs that are well characterized include del8p23, which includes the cardiac transcription factor GATA4 and manifests with a range of CHD along with developmental delay 36 ; del7q11, the cause of William Syndrome, wherein the cardiac disease consists of supravalvar aortic and pulmonary stenosis and results from haploinsufficiency for Elastin 37, 38 ; del 11q24-25 resulting in Jacobsen Syndrome 39, 40 .…”

Section: Established Genetic Contributions To Chdmentioning

confidence: 99%

Genetics and Genomics of Congenital Heart Disease

Zaidi

Brueckner

2017

Circulation Research

403

432

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Congenital heart disease is the most common birth defect, and due to major advances in medical and surgical management, there are now more adults living with CHD than children. Until recently, the cause of the majority of CHD was unknown. Advances in genomic technologies have discovered the genetic etiology of a significant fraction of CHD, while at the same time pointing to remarkable complexity in CHD genetics. This review will focus on the evidence for genetic causes underlying CHD and discuss data supporting both monogenic and complex genetic mechanisms underlying CHD. The discoveries from CHD genetic studies draw attention to biological pathways that simultaneously open the door to a better understanding of cardiac development, and impact clinical care of CHD patients. Finally, we address clinical genetic evaluation of patients and families affected by CHD.

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“…We speculated that W118R in ENU706 mice might also have a gain-of-function as other T-box mutations. More interestingly, recent study indicated that it also binds to chromatin that may function epigenetically [36]. Another study proposed that cortical development was regulated by mesodermal expression of Tbx1 [37].…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel ENU-Induced Mutation in Mouse Tbx1 Linked to Human DiGeorge Syndrome

Chen

Xue

et al. 2016

Neural Plasticity

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The patients with DiGeorge syndrome (DGS), caused by deletion containing dozens of genes in chromosome 22, often carry cardiovascular problem and hearing loss associated with chronic otitis media. Inside the deletion region, a transcription factor TBX1 was highly suspected. Furthermore, similar DGS phenotypes were found in the Tbx1 heterozygous knockout mice. Using ENU-induced mutagenesis and G1 dominant screening strategy, here we identified a nonsynonymous mutation p.W118R in T-box of TBX1, the DNA binding domain for transcription activity. The mutant mice showed deficiency of inner ear functions, including head tossing and circling, plus increased hearing threshold determined by audiometry. Therefore, our result further confirms the pathogenic basis of Tbx1 in DGS, points out the crucial role of DNA binding activity of TBX1 for the ear function, and provides additional animal model for studying the DGS disease mechanisms.

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Rebalancing gene haploinsufficiency in vivo by targeting chromatin

Cited by 70 publications

References 39 publications

BRACHYURY directs histone acetylation to target loci during mesoderm development

BRACHYURY directs histone acetylation to target loci during mesoderm development

Genetics and Genomics of Congenital Heart Disease

Identification of a Novel ENU-Induced Mutation in Mouse Tbx1 Linked to Human DiGeorge Syndrome

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