Forkhead box protein D2 suppresses colorectal cancer by reprogramming enhancer interactions

Kim, Hyo-Min; Kang, Byung Ha; Park, S. E.; Park, Hyorim; Kim, Chan Johng; Lee, Hyeonji; Yoo, Mijoung; Kweon, Mi‐Na; Im, Sin Hyeog; Kim, Taeil; Roh, Tae-Young

doi:10.1093/nar/gkad361

Cited by 6 publications

References 53 publications

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The histone methyltransferase KMT2D is essential for embryo implantation via regulating precise differentiation of endometrial cells

Kobayashi,

Tajika,

Kohmaru

et al. 2024

Cell Death Discov.

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Embryo implantation failures are a major challenge in reproductive medicine, but the underlying mechanism remains poorly understood. Successful implantation requires dynamic remodeling of the endometrium through integrated proliferation and differentiation of endometrial cells including luminal epithelial, glandular epithelial, and stromal cells. Conversely, their disruption causes infertility. Spatiotemporal control of transcription is required for these processes; however, the underlying epigenetic regulation is largely unknown. In this study, we examined expression data from the human endometrium during implantation and discovered that expression of the histone lysine methyltransferase KMT2D was significantly suppressed in patients with recurrent implantation failure. Further study revealed that uterine deletion of Kmt2d in mice caused infertility due to implantation failure. Morphological analysis discovered a reduction in the number of uterine glands and aberrant differentiation of the luminal and glandular epithelium into stratified phenotypes in Kmt2d knockout uteri. Administration of leukemia inhibitory factor protein, which is expressed in uterine glands and is essential for implantation, did not rescue implantation failure in Kmt2d knockout mice, suggesting that infertility was not solely due to uterine gland dysfunction. RNA sequencing analysis revealed that Kmt2d knockout uteri displayed suppressed expression of genes involved in ion homeostasis, which may affect the uterine luminal morphology. Our study suggests that KMT2D plays an essential role in facilitating successful embryo implantation by regulating the coordinated differentiation of endometrial cells, providing valuable insights into unexplained implantation failures in women.

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The histone methyltransferase KMT2D is essential for embryo implantation via regulating precise differentiation of endometrial cells

Kobayashi,

Tajika,

Kohmaru

et al. 2024

Cell Death Discov.

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Isorhynchophylline attenuates proliferation and migration of synovial fibroblasts via the FOXC1/β-catenin axis

Wu,

Bian,

Fei

et al. 2023

Autoimmunity

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Integrative multi-omics increase resolution of the sea urchin posterior gut gene regulatory network at single cell level

Voronov

Paganos

Magri

et al. 2023

Preprint

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Gene regulatory networks (GRNs) can be used to describe gene interactions of various complex biological processes such as embryonic development, regeneration and disease. The purple sea urchinStrongylocentrotus purpuratusendomesoderm developmental GRN has been a subject of multiple studies. Traditional approaches to drafting GRNs require embryological knowledge pertaining to the cell type families, information on the regulatory genes that control the regulatory state of the cell type family, causal data from gene knockdown experiments and validations of the identified interactions by cis-regulatory analysis, which helps identify the cis-regulatory modules (CRMs) of the regulatory genes. These approaches lacked information on whether these gene interactions are direct. The advent of a multitude of omics approaches involving next-generation sequencing (-seq) allows to obtain the necessary information for GRN drafting, including whether the interactions are direct. Here we present a combinatorial omics method for in silico GRN drafting at high resolution, using i) a single cell RNA-seq derived cell atlas highlighting the 2 day post fertilization (dpf) sea urchin gastrula cell type families, as well as the genes expressed at single cell level, ii) a set of putative CRMs and transcription factor (TF) binding sites obtained from chromatin accessibility ATAC-seq data, and iii) interactions directionality obtained from differential bulk RNA-seq following knockdown of the TF Sp-Pdx1, a key regulator of gut patterning in sea urchins. Using this method, we draft the GRN forSp-Pdx1positive cells in the 2 dpf gastrula embryonic gut and show that the previously studied GRN of the sea urchin embryonic hindgut is deeper and more complex than previously indicated.

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Forkhead box protein D2 suppresses colorectal cancer by reprogramming enhancer interactions

Cited by 6 publications

References 53 publications

The histone methyltransferase KMT2D is essential for embryo implantation via regulating precise differentiation of endometrial cells

The histone methyltransferase KMT2D is essential for embryo implantation via regulating precise differentiation of endometrial cells

Isorhynchophylline attenuates proliferation and migration of synovial fibroblasts via the FOXC1/β-catenin axis

Integrative multi-omics increase resolution of the sea urchin posterior gut gene regulatory network at single cell level

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