Navigating the DNA methylation landscape of cancer

Trends in Genetics, Journal Year: 2021, Volume and Issue: 37(11), P. 1012 - 1027

Published: June 10, 2021

DNA methylation is an important epigenetic modification that defines the properties of cells. Genome-wide hypomethylation, as well hypermethylation CpG islands associated with tumor suppressor genes and developmental regulators, are characteristics cancer cells.DNA methyltransferases normally exist in inactive form their localization activation regulated by interaction unique histone modifications at sites.Changes patterns carcinogenesis progress gradually cell proliferation. hypomethylation found blocks called partially methylated domains (PMDs) it frequently occurs solo-WCGW sequences have no nearby adjacent to A or C.CpG island primarily targets promoters characterized low gene expression marked H3K27m3, replacement ensuring more stable repression. a chemical type lineage through control genome stability. Disruption mechanisms causes variety diseases, including cancer. Cancer cells aberrant (i.e., genome-wide site-specific hypermethylation), mainly targeting regulatory elements. In particular, early findings (TSGs) led proposal model which promotes cellular oncogenesis TSGs silencing. However, recent analyses revealed this classical needs be reconsidered. review, we will discuss molecular abnormalities therapeutic potential. plays role regulation [1.Yisraeli J. et al.Muscle-specific chimeric actin gene.Cell. 1986; 46: 409-416Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 2.Busslinger M. al.DNA globin expression.Cell. 1983; 34: 197-206Abstract 3.Siegfried Z. represses transcription vivo.Nat. Genet. 1999; 22: 203-206Crossref (268) Scholar], genomic imprinting [4.Li E. al.Role for imprinting.Nature. 1993; 366: 362-365Crossref (1684) 5.Stöger R. al.Maternal-specific imprinted mouse Igf2r locus identifies expressed carrying signal.Cell. 73: 61-71Abstract 6.Ferguson-Smith A.C. al.Parental-origin-specific H19 gene.Nature. 362: 751-755Crossref X chromosome inactivation [7.Mohandas T. al.Reactivation human chromosome: evidence methylation.Science. 1981; 211: 393-396Crossref Scholar,8.Wolf S.F. al.Methylation hypoxanthine phosphoribosyltransferase on implications X-chromosome inactivation.Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 2806-2810Crossref transposon (see Glossary) silencing [9.Walsh C.P. al.Transcription IAP endogenous retroviruses constrained cytosine methylation.Nat. 1998; 20: 116-117Crossref (808) stability [10.Eden al.Chromosomal instability tumors promoted hypomethylation.Science. 2003; 300: 455Crossref (1008) Scholar,11.Karpf A.R. Matsui Genetic disruption methyltransferase enzymes induces chromosomal cells.Cancer Res. 2005; 65: 8635-8639Crossref (190) Scholar]. catalyzed three enzymes, DNMT1, DNMT3A, DNMT3B (Figure 1). De novo (DNMTs) DNMT3A 3B (Box 1), while established maintained daughter maintenance mechanism during proliferation 2). Both de normal development. DNMT1 DNMT3A/3B double knockout (KO) embryos show significant growth inhibition lethal before mid-gestation [12.Li al.Targeted mutation results embryonic lethality.Cell. 1992; 69: 915-926Abstract (3073) Scholar,13.Okano Dnmt3a Dnmt3b essential mammalian development.Cell. 99: 247-257Abstract (4122) contrast, not necessarily required stem (ES) cells; even when completely lost combined KO DNMTs Dnmt1, Dnmt3a, Dnmt3b, there minimal change phenotype undifferentiated ES [14.Tsumura al.Maintenance self-renewal ability absence Dnmt3b.Genes Cells. 2006; 11: 805-814Crossref (380) Although modification, also several pathways demethylation these play various biological contexts 3). cells, most methylated, but shores (the region within 2 kb islands) exceptionally hypomethylated [15.Irizarry R.A. al.The colon methylome shows similar hypo- conserved tissue-specific shores.Nat. 2009; 41: 178-186Crossref (1528) Scholar,16.Doi al.Differential tissue- cancer-specific distinguishes induced pluripotent fibroblasts.Nat. 1350-1353Crossref (892) Many regions function elements regulate expression, such enhancers. addition, systematic analysis unmethylated ligands has binding many factors [17.Yin Y. al.Impact specificities factors.Science. 2017; 356eaaj2239Crossref (373) Recently, broad were reported canyons [18.Jeong al.Large Dnmt3a.Nat. 2014; 17-23Crossref (203) Scholar] valleys [19.Xie W. al.Epigenomic multilineage differentiation cells.Cell. 2013; 153: 1134-1148Abstract (475) either active mark H3K4me3 inhibitory H3K27me3.Figure 2Regulatory activity localization.Show full caption(A) H3, exists autoinhibitory state, ATRX-DNMT3A-DNMT3L (ADD) domain interacts catalytic (CD) inhibit binding. H3K4me0 ADD break autoinhibition activate DNMT3A. release H3K36me3 Pro-Trp-Trp-Pro (PWWP) promote body. It been H3K36Kme2 similarly regulates intergenic PWWP domain. (B) DNMT3A2 DNMT3B3, catalytically subunits, heterotetrameric 3B3-3A2-3A2-3B3. One two catalytic-like DNMT3B3 acidic patch nucleosome core particle, leading linker DNA. The chromatin (DNMT) complexes methylation, indicating importance patch, addition H3K36me2 me3.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Box 1De methylationMammalian sites methyltransferases, [13.Okano Scholar,125.Okano al.Cloning characterization family novel (cytosine-5) methyltransferases.Nat. 19: 219-220Crossref (1206) DNMT3 proteins composed N terminal region, central enzyme C 1) [126.Goll M.G. Bestor T.H. Eukaryotic methyltransferases.Annu. Rev. Biochem. 74: 481-514Crossref (1492) roles target enzymatic activity. proper [127.Ge Y.-Z. al.Chromatin domain.J. Biol. Chem. 2004; 279: 25447-25454Abstract (148) acts reader module recognize bind histones [128.Dhayalan reads 3 lysine 36 trimethylation guides methylation.J. 2010; 285: 26114-26120Abstract (330) Histone enriches body actively transcribed undergoing catalysis SETD2 protein (also RNAPII subunit B1), binds RNA polymerase II [129.Wagner E.J. Carpenter P.B. Understanding language Lys36 H3.Nat. Mol. Cell 2012; 13: 115-126Crossref (534) 130.Kizer K.O. al.A Set2 mediates couples H3 K36 transcript elongation.Mol. Cell. 25: 3305-3316Crossref (329) 131.Krogan N.J. Saccharomyces cerevisiae linked transcriptional elongation II.Mol. 23: 4207-4218Crossref (492) [132.Baubec al.Genomic profiling reveals genic methylation.Nature. 2015; 520: 243-247Crossref (350) Transcription- H3K36me3-mediated establishment oocyte [133.Xu Q. al.SETD2 maternal epigenome, development.Nat. 2019; 51: 844-856Crossref (64) Several studies shown differently. NSD1 NSD2 K36me2 using mesenchymal (MSCs) showed depends MSCs [134.Weinberg D.N. recruits shapes landscape.Nature. 573: 281-286Crossref (97) NSD1-mediated recently male germlines [135.Shirane K. al.NSD1-deposited directs germline counteracts Polycomb-associated silencing.Nat. 2020; 52: 1088-1098Crossref (15) Thus, H3K36me2-enriched H3K36me3-enriched bodies may specify DNMT3B, respectively, domain.The recognizes unmodified 4 [136.Ooi S.K. al.DNMT3L connects DNA.Nature. 2007; 448: 714-717Crossref (1040) crystal structure complex amino-terminal tail specific H3K4me0, H3K4me2 [137.Otani al.Structural basis recognition H3K4 status 3A ATRX–DNMT3–DNMT3L domain.EMBO Rep. 10: 1235-1241Crossref (250) 138.Guo X. insight into H3-induced DNMT3A.Nature. 517: 640-644Crossref (188) 139.Noh K.-M. al.Engineering histone-recognition alters landscape phenotypic features ESCs.Mol. 59: 89-103Abstract These consistent fact distribution mutually exclusive [138.Guo 140.Zhang Dnmt3a/3L guided tail.Nucleic Acids 38: 4246-4253Crossref (243) 141.Li B.-Z. al.Histone tails allosterically activating methyltransferase.Cell 2011; 21: 1172-1181Crossref (81) 142.Guibert al.Global erasure primordial germ cells.Genome 633-641Crossref (224) Moreover, stimulates vitro Scholar,140.Zhang Scholar,141.Li tail, directly inhibits (CD). H3K4me3, disrupts ADD-CD cancels 2A) This would ensure suppression unfavorable H3K4me3-marked promoter, recruited.Figure 3Ubiquitin-like, containing PHD RING finger 1 (UHRF1)-dependent ubiquitin signaling orchestrates methylation.Show captionDuring replication, converted hemi-methylated only parent strand methylated. UHRF1 specifically Lys residues terminus PCNA-associated factor 15 (PAF15) dual monoubiquitylation. Ubiquitinated PAF15 RFTS DNMT1. Hemi-methylated left after passage replication machinery fully DNA, probably via UHRF1-dependent monoubiquitination H3. between USP7 indicates act deubiquitinating antagonizes UHRF1.View 2Maintenance methylationProper require factors. Early demonstrated colocalizes PCNA foci [143.Chuang L. al.Human DNA-(cytosine-5) methyltransferase-PCNA p21WAF1.Science. 1997; 277: 1996-2000Crossref (755) later was DNMT1/PCNA [144.Spada F. al.DNMT1 its cells.J. 176: 565-571Crossref (145) Scholar,145.Easwaran H.P. al.Replication-independent loading Dnmt1 G2 M phases.EMBO 5: 1181-1186Crossref (130) Ubiquitin-like, (UHRF1), ICPB90 humans Np95 mice, critical [116.Sharif SRA inheritance recruiting 450: 908-912Crossref (830) Scholar,117.Bostick al.UHRF1 Plays maintaining cells.Science. 317: 1760-1764Crossref (867) SET- RING-associated (SRA) [146.Arita al.Recognition base-flipping mechanism.Nature. 2008; 455: 818-821Crossref (335) 147.Hashimoto H. flips 5-methylcytosine out helix.Nature. 826-829Crossref (300) 148.Avvakumov G.V. UHRF1.Nature. 822-825Crossref (331) accumulates recruit Recent indicated E3 ligase efficient methylation. Upon SRA-mediated mono-ubiquitylates Lys14-, Lys18, and/or 23 [115.Nishiyama al.Uhrf1-dependent H3K23 ubiquitylation replication.Nature. 502: 249-253Crossref (206) Scholar,149.Ishiyama al.Structure complexed two-mono-ubiquitin maintenance.Mol. 68: 350-360Abstract Scholar,150.Qin requires interacting motif (UIM) ubiquitination.Cell 911-929Crossref (127) Hemi-methyl-DNA accessibility [120.Harrison J.S. al.Hemi-methylated allosteric UHRF1.eLife. 2016; 5e17101Crossref Scholar,151.Fang opens closed conformation facilitate recognition.Nat. Commun. 7: 11197Crossref (66) Ubiquitin-like (UBL) contributes E2 ubiquitin-conjugating Ubch5a/UBE2D1 [123.Foster B.M. al.Critical UBL stimulating toward chromatin.Mol. 2018; 72: 739-752Abstract (31) Scholar,124.DaRosa P.A. bifunctional DNA-dependent ubiquitylation.Mol. 753-765Abstract (29) Multiple mono-ubiquitylated turn recognized bound modules DNMT1-RFTS [118.Li mechanistic insights UHRF1-mediated methylation.Nucleic 3218-3231Crossref (53) previously recruitment [152.Leonhardt sequence nuclei.Cell. 71: 865-873Abstract (784) proposed pocket [153.Takeshita (Dnmt1).Proc. 108: 9055-9059Crossref Scholar,154.Syeda focus (RFTS) DNA-competitive inhibitor Dnmt1.J. 286: 15344-15351Abstract (76) Importantly, enhances [149.Ishiyama presumably gross conformational opening site. data indicate ubiquitylated platform DNMT1.Recently, emerged another substrate multiple mono-ubiquitylation [121.Nishiyama al.Two distinct modes 1222Crossref (25) Scholar,155.Karg al.Ubiquitome ubiquitination 429: 3814-3824Crossref (19) 2VRTK5, extreme PAF15, manner ARTK suggesting recognizing end proteins. During S phase, undergoes evolutionarily replication-coupled front face inner ring exits clamp from back [156.March al.p15PAF modulates sliding surface.Nucleic 9816-9828Crossref (7) could PCNA, facilitating 3).Box 3DNA demethylationDuring development, pattern fluctuates dynamically [142.Guibert Scholar,157.Hajkova P. dynamics reprogramming line.Nature. 452: 877-881Crossref (482) Scholar,158.Hackett J.A. al.Germline imprint 5-hydroxymethylcytosine.Science. 339: 448-452Crossref (511) particularly preimplantation (PGC) setting up states erasing parental-origin-specific imprints developing PGCs [159.Lee al.Erasing memory clone produced day 11.5 cells.Development. 2002; 129: 1807-1817Crossref (50) Scholar,160.Hill demethylation, Tet 5-hydroxymethylcytosine reprogramming: emerging story.Genomics. 104: 324-333Crossref (101) different pathways: (i) replication-dependent dilution marks [161.Kagiwada al.Replication-coupled passive mice.EMBO 32: 340-353Crossref (197) 162.Ohno 140: 2892-2903Crossref (52) 163.Seisenberger cells.Mol. 48: 849-862Abstract (575) 164.Kurimoto al.Complex orchestrated Blimp1 specification mice.Gene Dev. 1617-1635Crossref (ii) Ten-eleven Translocation (TET)-dependent [165.Yamaguchi Tet1 504: 460-464Crossref 166.Yamaguchi al.Tet1 controls meiosis regulating meiotic expression.Nature. 492: 443-447Crossref (182) 167.Wu Zhang Reversing methylati

Language: Английский

---

Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease

Cell, Journal Year: 2018, Volume and Issue: 175(2), P. 372 - 386.e17

Published: Sept. 27, 2018

Highlights•Single-cell census of the colonic mesenchyme reveals unexpected heterogeneity•Identification crypt niche mesenchymal cell expressing SOX6 and Wnts•Definition fundamental aspects remodeling in colitis•Analysis colitis-associated cells pathogenicity driversSummaryIntestinal play essential roles epithelial homeostasis, matrix remodeling, immunity, inflammation. But extent heterogeneity within these processes remains unknown. Using unbiased single-cell profiling over 16,500 cells, we reveal four subsets fibroblasts divergent transcriptional regulators functional pathways, addition to pericytes myofibroblasts. We identified a population located proximity crypts SOX6, F3 (CD142), WNT genes for stem function. In colitis, observed dysregulation this emergence an activated population. This subset expressed TNF superfamily member 14 (TNFSF14), fibroblastic reticular cell-associated genes, IL-33, Lysyl oxidases. Further, it induced factors that impaired proliferation maturation contributed oxidative stress disease severity vivo. Our work defines how remodels fuel inflammation barrier dysfunction IBD.Graphical abstract

Language: Английский

---

T Helper Cell Cytokines Modulate Intestinal Stem Cell Renewal and Differentiation

Cell, Journal Year: 2018, Volume and Issue: 175(5), P. 1307 - 1320.e22

Published: Nov. 1, 2018

Language: Английский

---

Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Aug. 7, 2020

Abstract Many important cell types in adult vertebrates have a mesenchymal origin, including fibroblasts and vascular mural cells. Although their biological importance is undisputed, the level of heterogeneity within between organs, while appreciated, has not been analyzed detail. Here, we compare single-cell transcriptional profiles cells across four murine muscular organs: heart, skeletal muscle, intestine bladder. We reveal gene expression signatures that demarcate from provide molecular for subtype identification. observe striking inter- intra-organ amongst fibroblasts, primarily reflecting differences extracellular matrix components. Fibroblast subtypes localize to discrete anatomical positions offering novel predictions about physiological function(s) regulatory signaling circuits. Our data shed new light on diversity poorly defined classes foundation improved understanding roles pathological processes.

Language: Английский

---

Cell fate specification and differentiation in the adult mammalian intestine

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 22(1), P. 39 - 53

Published: Sept. 21, 2020

Language: Английский

---

Cancer-associated fibroblasts in gastrointestinal cancer

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2019, Volume and Issue: 16(5), P. 282 - 295

Published: Feb. 18, 2019

Language: Английский

---

Spatiotemporal analysis of human intestinal development at single-cell resolution

Cell, Journal Year: 2021, Volume and Issue: 184(3), P. 810 - 826.e23

Published: Jan. 7, 2021

Development of the human intestine is not well understood. Here, we link single-cell RNA sequencing and spatial transcriptomics to characterize intestinal morphogenesis through time. We identify 101 cell states including epithelial mesenchymal progenitor populations programs linked key morphogenetic milestones. describe principles crypt-villus axis formation; neural, vascular, morphogenesis, immune population developing gut. differentiation hierarchies fibroblast myofibroblast subtypes diverse functions for these as vascular niche cells. pinpoint origins Peyer's patches gut-associated lymphoid tissue (GALT) location-specific programs. use our resource present an unbiased analysis morphogen gradients that direct sequential waves cellular define cells locations rare developmental disorders. compile a publicly available online resource, spatio-temporal fetal development (STAR-FINDer), facilitate further work.

Language: Английский

---

Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet

Cell, Journal Year: 2019, Volume and Issue: 178(5), P. 1115 - 1131.e15

Published: Aug. 1, 2019

Language: Английский

---

Distinct Mesenchymal Cell Populations Generate the Essential Intestinal BMP Signaling Gradient

Cell stem cell, Journal Year: 2020, Volume and Issue: 26(3), P. 391 - 402.e5

Published: Feb. 21, 2020

Language: Английский

---

Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium

Nature, Journal Year: 2019, Volume and Issue: 571(7765), P. 398 - 402

Published: July 10, 2019

Language: Английский

---