Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms

Yoo, Kyung Hyun; Oh, Seungmin; Kang, Keunsoo; Wang, Chaochen; Robinson, Gertraud W.; Ge, Kai; Hennighausen, Lothar

doi:10.1128/mcb.00089-16

Cited by 27 publications

(32 citation statements)

References 57 publications

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“…UTX physically associates with KMT2D and CBP, which function in enhancer activation through H3K27 acetylation (53,(65)(66)(67)(68). UTX has previously been localized to both promoters and enhancers in mouse mammary tissue (57) and has been correlated with ES cell enhancer activation (69). We found UTX at a large percentage of distal elements ( Fig.…”

Section: Discussionsupporting

confidence: 55%

“…However, UTX demethylation is not crucial for NC cellular development as KI/KI catalytic point mutation lacks any discernible craniofacial phenotype. UTX-mediated demethylation is required in vivo for muscle regeneration and antiviral immunity; however, many developmental decisions do not require catalytic activity including mesoderm induction, mammary luminal differentiation, T-cell differentiation, and gross embryonic development (17,28,41,42,52,(56)(57)(58). Furthermore, two Kabuki causative human point mutations, K188R and N910S, exhibit normal H3K27me3 demethylation and produce the disorder through disruption of alternative, demethylase-independent UTX function.…”

Section: Discussionmentioning

confidence: 99%

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UTX-guided neural crest function underlies craniofacial features of Kabuki syndrome

Shpargel

Starmer

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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103

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Kabuki syndrome, a congenital craniofacial disorder, manifests from mutations in an X-linked histone H3 lysine 27 demethylase (UTX/KDM6A) or a H3 lysine 4 methylase (KMT2D). However, the cellular and molecular etiology of histone-modifying enzymes in craniofacial disorders is unknown. We now establish Kabuki syndrome as a neurocristopathy, whereby the majority of clinical features are modeled in mice carrying neural crest (NC) deletion of UTX, including craniofacial dysmorphism, cardiac defects, and postnatal growth retardation. Female UTX NC knockout (FKO) demonstrates enhanced phenotypic severity over males (MKOs), due to partial redundancy with UTY, a Y-chromosome demethylase-dead homolog. Thus, NC cells may require demethylase-independent UTX activity. Consistently, Kabuki causative point mutations upstream of the JmjC domain do not disrupt UTX demethylation. We have isolated primary NC cells at a phenocritical postmigratory timepoint in both FKO and MKO mice, and genome-wide expression and histone profiling have revealed UTX molecular function in establishing appropriate chromatin structure to regulate crucial NC stem-cell signaling pathways. However, the majority of UTX regulated genes do not experience aberrations in H3K27me3 or H3K4me3, implicating alternative roles for UTX in transcriptional control. These findings are substantiated through demethylase-dead knockin mutation of UTX, which supports appropriate facial development.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

UTX-guided neural crest function underlies craniofacial features of Kabuki syndrome

Shpargel

Starmer

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

103

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“…However, multiple studies reported that UTX controls cell differentiation and animal development independently from its H3K27 demethylase activity (Faralli et al, 2016; Shpargel et al, 2014; Vandamme et al, 2012; Wang et al, 2012; Yoo et al, 2016). These studies indicate that UTX enzymatic activity is dispensable for enhancer activation and cell-type specific gene expression and that UTX likely functions on enhancers through association with KMT2C and/or KMT2D.…”

Section: Kmt2d Is a Prominent Enhancer H3k4 Mono-methyltransferasementioning

confidence: 99%

Histone H3 lysine 4 methyltransferase KMT2D

Froimchuk

Jang

2017

Gene

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229

214

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Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and MLL2 in humans and Mll4 in mice, belongs to a family of mammalian histone H3 lysine 4 (H3K4) methyltransferases. It is a large protein over 5,500 amino acids in size and is partially functionally redundant with KMT2C. KMT2D is widely expressed in adult tissues and is essential for early embryonic development. The C-terminal SET domain is responsible for its H3K4 methyltransferase activity and is necessary for maintaining KMT2D protein stability in cells. KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. KMT2D is a major mammalian H3K4 mono-methyltransferase and co-localizes with lineage determining transcription factors on transcriptional enhancers. It is required for the binding of histone H3K27 acetyltransferases CBP and p300 on enhancers, enhancer activation and cell-type specific gene expression during differentiation. KMT2D plays critical roles in regulating development, differentiation, metabolism, and tumor suppression. It is frequently mutated in developmental diseases, such as Kabuki syndrome and congenital heart disease, and various forms of cancer. Further understanding of the mechanism through which KMT2D regulates gene expression will reveal why KMT2D mutations are so harmful and may help generate novel therapeutic approaches.

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“…MLL2 also involved into the carcinogenesis of oral cancer by next‐generation sequencing (NGS), specifically, frequently altered in gingivo‐buccal oral squamous cell carcinoma . MLL2 also disrupt enhancer activity and transcription of genes to destruct cell stability during carcinogenesis …”

Section: Discussionmentioning

confidence: 99%

Tumor‐infiltrating lymphocyte‐derived MLL2 independently predicts disease‐free survival for patients with early‐stage oral squamous cell carcinoma

Zhu

Ding

et al. 2019

J Oral Pathology Medicine

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Background MLL2 (mixed‐lineage leukemia 2) is recognized as an essential role in regulating histone 3 lysine 4 tri‐methylation (H3K4me3) in mammalian cells. It is frequently mutated to promote developmental diseases and tumor initiation. However, the expression pattern of MLL2 and its clinical significance for patients with early‐stage oral squamous cell carcinoma (OSCC) remain totally unknown. Methods Eighty‐five samples of primary early‐stage OSCC were enrolled in this retrospective study, and immunohistochemistry (IHC) was performed to detect the spatial pattern of MLL2. The diagnostic and prognostic value of MLL2 were assessed. Results MLL2 was widely expressed in tumor cells (TCs), fibroblast‐like cells (FLCs), and tumor‐infiltrating lymphocytes (TILs), both in tumor center and invasive tumor front, and showed no distributive heterogeneity. Moreover, regardless of cell types and microlocalization, patients with high expressed MLL2 had increased depth invasion of tumor (DOI). Besides, upregulation of MLL2TC and MLL2TIL in tumor center were both associated with poor differentiation, but showed no correlation with tumor growth with comparable Ki‐67 levels. Prognostic analysis indicated that early‐stage OSCC patients with enhanced MLL2TIL in invasive tumor front were susceptible to occur postoperative metastasis and recurrence. Indeed, patients with higher expressed MLL2TIL showed shorter overall survival (OS) and disease‐free survival (DFS), and MLL2TIL in invasive tumor front was an independent risk factor of DFS. Conclusion TIL‐derived MLL2 in invasive tumor front was an independent prognostic factor of DFS for early‐stage OSCC patients.

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Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms

Cited by 27 publications

References 57 publications

UTX-guided neural crest function underlies craniofacial features of Kabuki syndrome

UTX-guided neural crest function underlies craniofacial features of Kabuki syndrome

Histone H3 lysine 4 methyltransferase KMT2D

Tumor‐infiltrating lymphocyte‐derived MLL2 independently predicts disease‐free survival for patients with early‐stage oral squamous cell carcinoma

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