bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2021–12–19
seventeen papers selected by
Connor Rogerson, University of Cambridge, MRC Cancer Unit
  1. Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation.
  2. CoRE-ATAC: A deep learning model for the functional classification of regulatory elements from single cell and bulk ATAC-seq data.
  3. Androgen receptor and MYC equilibration centralizes on developmental super-enhancer.
  4. A systematic genome-wide account of binding sites for the model transcription factor Gcn4.
  5. Histone chaperone Nucleophosmin regulates transcription of key genes involved in oral tumorigenesis.
  6. Transcriptional network orchestrating regional patterning of cortical progenitors.
  7. Tfcancer: a manually curated database of transcription factors associated with human cancers.
  8. N6-methyladenosine (m6A) depletion regulates pluripotency exit by activating signaling pathways in embryonic stem cells.
  9. Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer.
  10. Phase separation of RNA-binding protein promotes polymerase binding and transcription.
  11. MED12 and BRD4 cooperate to sustain cancer growth upon loss of mediator kinase.
  12. Epigenetic loss of heterogeneity from low to high grade localized prostate tumours.
  13. Dynamic modulation of enhancer responsiveness by core promoter elements in living Drosophila embryos.
  14. CIDER: an interpretable meta-clustering framework for single-cell RNA-seq data integration and evaluation.
  15. Tissue-specific regulation of translational readthrough tunes functions of the traffic jam transcription factor.
  16. Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps.
  17. 5-Hydroxymethylcytosine-mediated active demethylation is required for mammalian neuronal differentiation and function.
  1. Cell Rep. 2021 Dec 14. pii: S2211-1247(21)01620-X. [Epub ahead of print]37(11): 110124
    Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation.
    Jun Li, Beisi Xu, Minghong He, Xinying Zong, Trevor Cunningham, Cher Sha, Yiping Fan, Richard Cross, Jacob H Hanna, Yongqiang Feng.
      Regulatory T (Treg) cells play crucial roles in suppressing deleterious immune response. Here, we investigate how Treg cells are mechanistically induced in vitro (iTreg) and stabilized via transcriptional regulation of Treg lineage-specifying factor Foxp3. We find that acetylation of histone tails at the Foxp3 promoter is required for inducing Foxp3 transcription. Upon induction, histone acetylation signals via bromodomain-containing proteins, particularly targets of inhibitor JQ1, and sustains Foxp3 transcription via a global or trans effect. Subsequently, Tet-mediated DNA demethylation of Foxp3 cis-regulatory elements, mainly enhancer CNS2, increases chromatin accessibility and protein binding, stabilizing Foxp3 transcription and obviating the need for the histone acetylation signal. These processes transform stochastic iTreg induction into a stable cell fate, with the former sensitive and the latter resistant to genetic and environmental perturbations. Thus, sequential histone acetylation and DNA demethylation in Foxp3 induction and maintenance reflect stepwise mechanical switches governing iTreg cell lineage specification.
    Keywords:  DNA demethylation; Foxp3; cell fate; histone acetylation; regulatory T cells; transcription
    DOI:  https://doi.org/10.1016/j.celrep.2021.110124
  2. PLoS Comput Biol. 2021 Dec 13. 17(12): e1009670
    CoRE-ATAC: A deep learning model for the functional classification of regulatory elements from single cell and bulk ATAC-seq data.
    Asa Thibodeau, Shubham Khetan, Alper Eroglu, Ryan Tewhey, Michael L Stitzel, Duygu Ucar.
      Cis-Regulatory elements (cis-REs) include promoters, enhancers, and insulators that regulate gene expression programs via binding of transcription factors. ATAC-seq technology effectively identifies active cis-REs in a given cell type (including from single cells) by mapping accessible chromatin at base-pair resolution. However, these maps are not immediately useful for inferring specific functions of cis-REs. For this purpose, we developed a deep learning framework (CoRE-ATAC) with novel data encoders that integrate DNA sequence (reference or personal genotypes) with ATAC-seq cut sites and read pileups. CoRE-ATAC was trained on 4 cell types (n = 6 samples/replicates) and accurately predicted known cis-RE functions from 7 cell types (n = 40 samples) that were not used in model training (mean average precision = 0.80, mean F1 score = 0.70). CoRE-ATAC enhancer predictions from 19 human islet samples coincided with genetically modulated gain/loss of enhancer activity, which was confirmed by massively parallel reporter assays (MPRAs). Finally, CoRE-ATAC effectively inferred cis-RE function from aggregate single nucleus ATAC-seq (snATAC) data from human blood-derived immune cells that overlapped with known functional annotations in sorted immune cells, which established the efficacy of these models to study cis-RE functions of rare cellswithout the need for cell sorting. ATAC-seq maps from primary human cells reveal individual- and cell-specific variation in cis-RE activity. CoRE-ATAC increases the functional resolution of these maps, a critical step for studying regulatory disruptions behind diseases.
    DOI:  https://doi.org/10.1371/journal.pcbi.1009670
  3. Nat Commun. 2021 Dec 15. 12(1): 7308
    Androgen receptor and MYC equilibration centralizes on developmental super-enhancer.
    Haiyang Guo, Yiming Wu, Mannan Nouri, Sandor Spisak, Joshua W Russo, Adam G Sowalsky, Mark M Pomerantz, Zhao Wei, Keegan Korthauer, Ji-Heui Seo, Liyang Wang, Seiji Arai, Matthew L Freedman, Housheng Hansen He, Shaoyong Chen, Steven P Balk.
      Androgen receptor (AR) in prostate cancer (PCa) can drive transcriptional repression of multiple genes including MYC, and supraphysiological androgen is effective in some patients. Here, we show that this repression is independent of AR chromatin binding and driven by coactivator redistribution, and through chromatin conformation capture methods show disruption of the interaction between the MYC super-enhancer within the PCAT1 gene and the MYC promoter. Conversely, androgen deprivation in vitro and in vivo increases MYC expression. In parallel, global AR activity is suppressed by MYC overexpression, consistent with coactivator redistribution. These suppressive effects of AR and MYC are mitigated at shared AR/MYC binding sites, which also have markedly higher levels of H3K27 acetylation, indicating enrichment for functional enhancers. These findings demonstrate an intricate balance between AR and MYC, and indicate that increased MYC in response to androgen deprivation contributes to castration-resistant PCa, while decreased MYC may contribute to responses to supraphysiological androgen therapy.
    DOI:  https://doi.org/10.1038/s41467-021-27077-y
  4. Genome Res. 2021 Dec 16. pii: gr.276080.121. [Epub ahead of print]
    A systematic genome-wide account of binding sites for the model transcription factor Gcn4.
    Christopher T Coey, David J Clark.
      Sequence-specific DNA-binding transcription factors are central to gene regulation. They are often associated with consensus binding sites that predict far more genomic sites than are bound in vivo. One explanation is that most sites are blocked by nucleosomes, such that only sites in nucleosome-depleted regulatory regions are bound. We compared the binding of the yeast transcription factor Gcn4 in vivo using published ChIP-seq data (546 sites) and in vitro, using a modified SELEX method ("G-SELEX"), which utilizes short genomic DNA fragments to quantify binding at all sites. We confirm that Gcn4 binds strongly to an AP-1-like sequence (TGACTCA) and weakly to half-sites. However, Gcn4 binds only some of the 1078 exact matches to this sequence, even in vitro. We show that there are only 166 copies of the high-affinity RTGACTCAY site (exact match) in the yeast genome, all occupied in vivo, largely independently of whether they are located in nucleosome-depleted or nucleosomal regions. Generally, RTGACTCAR/YTGACTCAY sites are bound much more weakly and YTGACTCAR sites are unbound, with biological implications for determining induction levels. We conclude that, to a first approximation, Gcn4 binding can be predicted using the high-affinity site, without reference to chromatin structure. We propose that transcription factor binding sites should be defined more precisely using quantitative data, allowing more accurate genome-wide prediction of binding sites and greater insight into gene regulation.
    DOI:  https://doi.org/10.1101/gr.276080.121
  5. Mol Cell Biol. 2021 Dec 13. MCB0066920
    Histone chaperone Nucleophosmin regulates transcription of key genes involved in oral tumorigenesis.
    Parijat Senapati, Aditya Bhattacharya, Sadhan Das, Suchismita Dey, Deepthi Sudarshan, Shyla G, Jyoti Vishwakarma, Surabhi Sudevan, Ravishankar Ramachandran, Tessy Thomas Maliekal, Tapas K Kundu.
      Nucleophosmin (NPM1) is a multifunctional histone chaperone that can activate acetylation-dependent transcription from chromatin templates in vitro. Acetylation of NPM1 by p300 has been shown to further enhance its transcription activation potential. Moreover, its total and acetylated pools are increased in oral squamous cell carcinoma. However, the role of NPM1 or its acetylated form (AcNPM1) in transcriptional regulation in cells and oral tumorigenesis is not fully elucidated. Using ChIP-seq analyses, we provide the first genome-wide profile of AcNPM1 and show that AcNPM1 is enriched at transcriptional regulatory elements. AcNPM1 co-occupies marks of active transcription at promoters and DNase I hypersensitive sites at enhancers. In addition, using a high-throughput protein interaction profiling approach, we show that NPM1 interacts with RNA Pol II, general transcription factors, mediator subunits, histone acetyltransferase complexes, and chromatin remodelers. NPM1 histone chaperone activity also contributes to its transcription activation potential. Further, NPM1 depletion leads to decreased AcNPM1 occupancy and reduced expression of genes required for proliferative, migratory and invasive potential of oral cancer cells. NPM1 depletion also abrogates the growth of orthotopic tumors in mice. Collectively, these results establish that AcNPM1 functions as a coactivator during during RNA polymerase II-driven transcription and regulates the expression of genes that promote oral tumorigenesis.
    DOI:  https://doi.org/10.1128/MCB.00669-20
  6. Proc Natl Acad Sci U S A. 2021 Dec 21. pii: e2024795118. [Epub ahead of print]118(51):
    Transcriptional network orchestrating regional patterning of cortical progenitors.
    Athéna R Ypsilanti, Kartik Pattabiraman, Rinaldo Catta-Preta, Olga Golonzhka, Susan Lindtner, Ke Tang, Ian R Jones, Armen Abnousi, Ivan Juric, Ming Hu, Yin Shen, Diane E Dickel, Axel Visel, Len A Pennachio, Michael Hawrylycz, Carol L Thompson, Hongkui Zeng, Iros Barozzi, Alex S Nord, John L Rubenstein.
      We uncovered a transcription factor (TF) network that regulates cortical regional patterning in radial glial stem cells. Screening the expression of hundreds of TFs in the developing mouse cortex identified 38 TFs that are expressed in gradients in the ventricular zone (VZ). We tested whether their cortical expression was altered in mutant mice with known patterning defects (Emx2, Nr2f1, and Pax6), which enabled us to define a cortical regionalization TF network (CRTFN). To identify genomic programming underlying this network, we performed TF ChIP-seq and chromatin-looping conformation to identify enhancer-gene interactions. To map enhancers involved in regional patterning of cortical progenitors, we performed assays for epigenomic marks and DNA accessibility in VZ cells purified from wild-type and patterning mutant mice. This integrated approach has identified a CRTFN and VZ enhancers involved in cortical regional patterning in the mouse.
    Keywords:  cortical patterning; epigenetics; progenitor cells; transcription factors
    DOI:  https://doi.org/10.1073/pnas.2024795118
  7. Bioinformatics. 2021 May 26. pii: btab405. [Epub ahead of print]
    Tfcancer: a manually curated database of transcription factors associated with human cancers.
    Qingqing Huang, Zhengtang Tan, Yanjing Li, Wenzhu Wang, Mei Lang, Changying Li, Zhiyun Guo.
       SUMMARY: Transcription factors (TFs) are critical regulation elements and its dysregulation can lead to a variety of cancers. However, currently, there are no such online resources for large-scale collection, storage and analysis of TF-cancer associations in those cancers. To fill this gap, we present a database called TFcancer (http://lcbb.swjtu.edu.cn/tfcancer/), which contains 3136 experimentally supported associations between 364 TFs and 33 TCGA cancers by manually curating more than 1800 literature. TFcancer mainly concentrates on four aspects: TF expression, molecular alteration, regulatory relationships between TFs and target genes, and biological processes and signaling pathways of TFs in cancers. TFcancer not only provides a user-friendly interface for browsing and searching but also allows flexible data downloading and user data submitting. It is believed that TFcancer is a helpful and valuable resource for researchers who seek to understand the functions and molecular mechanisms of TFs involved in human cancers.
    AVAILABILITY AND IMPLEMENTATION: The TFcancer are freely available at http://lcbb.swjtu.edu.cn/tfcancer/.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btab405
  8. Proc Natl Acad Sci U S A. 2021 Dec 21. pii: e2105192118. [Epub ahead of print]118(51):
    N6-methyladenosine (m6A) depletion regulates pluripotency exit by activating signaling pathways in embryonic stem cells.
    Kang-Xuan Jin, Rujuan Zuo, Konstantinos Anastassiadis, Arne Klungland, Carsten Marr, Adam Filipczyk.
      N6-methyladenosine (m6A) deposition on messenger RNA (mRNA) controls embryonic stem cell (ESC) fate by regulating the mRNA stabilities of pluripotency and lineage transcription factors (TFs) [P. J. Batista et al., Cell Stem Cell 15, 707-719 (2014); Y. Wang et al., Nat. Cell Biol. 16, 191-198 (2014); and S. Geula et al., Science 347, 1002-1006 (2015)]. If the mRNAs of these two TF groups become stabilized, it remains unclear how the pluripotency or lineage commitment decision is implemented. We performed noninvasive quantification of Nanog and Oct4 TF protein levels in reporter ESCs to define cell-state dynamics at single-cell resolution. Long-term single-cell tracking shows that immediate m6A depletion by Mettl3 knock-down in serum/leukemia inhibitory factor supports both pluripotency maintenance and its departure. This is mediated by differential and opposing signaling pathways. Increased FGF5 mRNA stability activates pErk, leading to Nanog down-regulation. FGF5-mediated coactivation of pAkt reenforces Nanog expression. In formative stem cells poised toward differentiation, m6A depletion activates both pErk and pAkt, increasing the propensity for mesendodermal lineage induction. Stable m6A depletion by Mettl3 knock-out also promotes pErk activation. Higher pErk counteracts the pluripotency exit delay exhibited by stably m6A-depleted cells upon differentiation. At single-cell resolution, we illustrate that decreasing m6A abundances activates pErk and pAkt-signaling, regulating pluripotency departure.
    Keywords:  formative stem cells; m6A; pluripotency; signaling; single-cell resolution
    DOI:  https://doi.org/10.1073/pnas.2105192118
  9. Nat Commun. 2021 Dec 13. 12(1): 7235
    Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer.
    Raquel Rouco, Olimpia Bompadre, Antonella Rauseo, Olivier Fazio, Rodrigue Peraldi, Fabrizio Thorel, Guillaume Andrey.
      Developmental genes are frequently controlled by multiple enhancers sharing similar specificities. As a result, deletions of such regulatory elements have often failed to reveal their full function. Here, we use the Pitx1 testbed locus to characterize in detail the regulatory and cellular identity alterations following the deletion of one of its enhancers (Pen). By combining single cell transcriptomics and an in-embryo cell tracing approach, we observe an increased fraction of Pitx1 non/low-expressing cells and a decreased fraction of Pitx1 high-expressing cells. We find that the over-representation of Pitx1 non/low-expressing cells originates from a failure of the Pitx1 locus to coordinate enhancer activities and 3D chromatin changes. This locus mis-activation induces a localized heterochrony and a concurrent loss of irregular connective tissue, eventually leading to a clubfoot phenotype. This data suggests that, in some cases, redundant enhancers may be used to locally enforce a robust activation of their host regulatory landscapes.
    DOI:  https://doi.org/10.1038/s41467-021-27492-1
  10. Nat Chem Biol. 2021 Dec 16.
    Phase separation of RNA-binding protein promotes polymerase binding and transcription.
    Wen Shao, Xianju Bi, Yixuan Pan, Boyang Gao, Jun Wu, Yafei Yin, Zhimin Liu, Mengyuan Peng, Wenhao Zhang, Xu Jiang, Wenlin Ren, Yanhui Xu, Zhongyang Wu, Kaili Wang, Ge Zhan, J Yuyang Lu, Xue Han, Tong Li, Jianlong Wang, Guohong Li, Haiteng Deng, Bing Li, Xiaohua Shen.
      An RNA-involved phase-separation model has been proposed for transcription control. However, the molecular links that connect RNA to the transcription machinery remain missing. Here we find that RNA-binding proteins (RBPs) constitute half of the chromatin proteome in embryonic stem cells (ESCs), some being colocalized with RNA polymerase (Pol) II at promoters and enhancers. Biochemical analyses of representative RBPs show that the paraspeckle protein PSPC1 inhibits the RNA-induced premature release of Pol II, and makes use of RNA as multivalent molecules to enhance the formation of transcription condensates and subsequent phosphorylation and release of Pol II. This synergistic interplay enhances polymerase engagement and activity via the RNA-binding and phase-separation activities of PSPC1. In ESCs, auxin-induced acute degradation of PSPC1 leads to genome-wide defects in Pol II binding and nascent transcription. We propose that promoter-associated RNAs and their binding proteins synergize the phase separation of polymerase condensates to promote active transcription.
    DOI:  https://doi.org/10.1038/s41589-021-00904-5
  11. Mol Cell. 2021 Dec 06. pii: S1097-2765(21)00995-3. [Epub ahead of print]
    MED12 and BRD4 cooperate to sustain cancer growth upon loss of mediator kinase.
    Dhanya Sooraj, Claire Sun, Anh Doan, Daniel J Garama, Marius V Dannappel, Danxi Zhu, Hui K Chua, Sylvia Mahara, Wan Amir Wan Hassan, Yeng Kwang Tay, Aleks Guanizo, Daniel Croagh, Zdenka Prodanovic, Daniel J Gough, Chunhua Wan, Ron Firestein.
      Mediator kinases (CDK8/19) are transcriptional regulators broadly implicated in cancer. Despite their central role in fine-tuning gene-expression programs, we find complete loss of CDK8/19 is tolerated in colorectal cancer (CRC) cells. Using orthogonal functional genomic and pharmacological screens, we identify BET protein inhibition as a distinct vulnerability in CDK8/19-depleted cells. Combined CDK8/19 and BET inhibition led to synergistic growth retardation in human and mouse models of CRC. Strikingly, depletion of CDK8/19 in these cells led to global repression of RNA polymerase II (Pol II) promoter occupancy and transcription. Concurrently, loss of Mediator kinase led to a profound increase in MED12 and BRD4 co-occupancy at enhancer elements and increased dependence on BET proteins for the transcriptional output of cell-essential genes. In total, this work demonstrates a synthetic lethal interaction between Mediator kinase and BET proteins and exposes a therapeutic vulnerability that can be targeted using combination therapies.
    Keywords:  BRD4; CDK8; Mediator complex; cancer; chromatin; combination therapy; enhancer; precision medicine; synthetic lethality; transcription
    DOI:  https://doi.org/10.1016/j.molcel.2021.11.015
  12. Nat Commun. 2021 Dec 15. 12(1): 7292
    Epigenetic loss of heterogeneity from low to high grade localized prostate tumours.
    Sebnem Ece Eksi, Alex Chitsazan, Zeynep Sayar, George V Thomas, Andrew J Fields, Ryan P Kopp, Paul T Spellman, Andrew C Adey.
      Identifying precise molecular subtypes attributable to specific stages of localized prostate cancer has proven difficult due to high levels of heterogeneity. Bulk assays represent a population-average, which mask the heterogeneity that exists at the single-cell level. In this work, we sequence the accessible chromatin regions of 14,424 single-cells from 18 flash-frozen prostate tumours. We observe shared chromatin features among low-grade prostate cancer cells are lost in high-grade tumours. Despite this loss, high-grade tumours exhibit an enrichment for FOXA1, HOXB13 and CDX2 transcription factor binding sites, indicating a shared trans-regulatory programme. We identify two unique genes encoding neuronal adhesion molecules that are highly accessible in high-grade prostate tumours. We show NRXN1 and NLGN1 expression in epithelial, endothelial, immune and neuronal cells in prostate cancer using cyclic immunofluorescence. Our results provide a deeper understanding of the active gene regulatory networks in primary prostate tumours, critical for molecular stratification of the disease.
    DOI:  https://doi.org/10.1038/s41467-021-27615-8
  13. Nucleic Acids Res. 2021 Dec 13. pii: gkab1177. [Epub ahead of print]
    Dynamic modulation of enhancer responsiveness by core promoter elements in living Drosophila embryos.
    Moe Yokoshi, Koji Kawasaki, Manuel Cambón, Takashi Fukaya.
      Regulatory interactions between enhancers and core promoters are fundamental for the temporal and spatial specificity of gene expression in development. The central role of core promoters is to initiate productive transcription in response to enhancer's activation cues. However, it has not been systematically assessed how individual core promoter elements affect the induction of transcriptional bursting by enhancers. Here, we provide evidence that each core promoter element differentially modulates functional parameters of transcriptional bursting in developing Drosophila embryos. Quantitative live imaging analysis revealed that the timing and the continuity of burst induction are common regulatory steps on which core promoter elements impact. We further show that the upstream TATA also affects the burst amplitude. On the other hand, Inr, MTE and DPE mainly contribute to the regulation of the burst frequency. Genome editing analysis of the pair-rule gene fushi tarazu revealed that the endogenous TATA and DPE are both essential for its correct expression and function during the establishment of body segments in early embryos. We suggest that core promoter elements serve as a key regulatory module in converting enhancer activity into transcription dynamics during animal development.
    DOI:  https://doi.org/10.1093/nar/gkab1177
  14. Genome Biol. 2021 Dec 13. 22(1): 337
    CIDER: an interpretable meta-clustering framework for single-cell RNA-seq data integration and evaluation.
    Zhiyuan Hu, Ahmed A Ahmed, Christopher Yau.
      Clustering of joint single-cell RNA-Seq (scRNA-Seq) data is often challenged by confounding factors, such as batch effects and biologically relevant variability. Existing batch effect removal methods typically require strong assumptions on the composition of cell populations being near identical across samples. Here, we present CIDER, a meta-clustering workflow based on inter-group similarity measures. We demonstrate that CIDER outperforms other scRNA-Seq clustering methods and integration approaches in both simulated and real datasets. Moreover, we show that CIDER can be used to assess the biological correctness of integration in real datasets, while it does not require the existence of prior cellular annotations.
    Keywords:  Clustering; Confounding factors; Single-cell RNA-Seq
    DOI:  https://doi.org/10.1186/s13059-021-02561-2
  15. Nucleic Acids Res. 2021 Dec 13. pii: gkab1189. [Epub ahead of print]
    Tissue-specific regulation of translational readthrough tunes functions of the traffic jam transcription factor.
    Prajwal Karki, Travis D Carney, Cristina Maracci, Andriy S Yatsenko, Halyna R Shcherbata, Marina V Rodnina.
      Translational readthrough (TR) occurs when the ribosome decodes a stop codon as a sense codon, resulting in two protein isoforms synthesized from the same mRNA. TR has been identified in several eukaryotic organisms; however, its biological significance and mechanism remain unclear. Here, we quantify TR of several candidate genes in Drosophila melanogaster and characterize the regulation of TR in the large Maf transcription factor Traffic jam (Tj). Using CRISPR/Cas9-generated mutant flies, we show that the TR-generated Tj isoform is expressed in a subset of neural cells of the central nervous system and is excluded from the somatic cells of gonads. Control of TR in Tj is critical for preservation of neuronal integrity and maintenance of reproductive health. The tissue-specific distribution of a release factor splice variant, eRF1H, plays a critical role in modulating differential TR of leaky stop codon contexts. Fine-tuning of gene regulatory functions of transcription factors by TR provides a potential mechanism for cell-specific regulation of gene expression.
    DOI:  https://doi.org/10.1093/nar/gkab1189
  16. Cell. 2021 Dec 08. pii: S0092-8674(21)01381-7. [Epub ahead of print]
    Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps.
    Bob Chen, Cherie' R Scurrah, Eliot T McKinley, Alan J Simmons, Marisol A Ramirez-Solano, Xiangzhu Zhu, Nicholas O Markham, Cody N Heiser, Paige N Vega, Andrea Rolong, Hyeyon Kim, Quanhu Sheng, Julia L Drewes, Yuan Zhou, Austin N Southard-Smith, Yanwen Xu, James Ro, Angela L Jones, Frank Revetta, Lynne D Berry, Hiroaki Niitsu, Mirazul Islam, Karin Pelka, Matan Hofree, Jonathan H Chen, Siranush Sarkizova, Kimmie Ng, Marios Giannakis, Genevieve M Boland, Andrew J Aguirre, Ana C Anderson, Orit Rozenblatt-Rosen, Aviv Regev, Nir Hacohen, Kenta Kawasaki, Toshiro Sato, Jeremy A Goettel, William M Grady, Wei Zheng, M Kay Washington, Qiuyin Cai, Cynthia L Sears, James R Goldenring, Jeffrey L Franklin, Timothy Su, Won Jae Huh, Simon Vandekar, Joseph T Roland, Qi Liu, Robert J Coffey, Martha J Shrubsole, Ken S Lau.
      Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.
    Keywords:  adenoma; colorectal cancer; cytotoxic; differentiation; metaplasia; multiplex; polyp; serrated; single-cell RNA-seq; stem cells
    DOI:  https://doi.org/10.1016/j.cell.2021.11.031
  17. Elife. 2021 Dec 17. pii: e66973. [Epub ahead of print]10
    5-Hydroxymethylcytosine-mediated active demethylation is required for mammalian neuronal differentiation and function.
    Elitsa Stoyanova, Michael Riad, Anjana Rao, Nathaniel Heintz.
      Although high levels of 5-hydroxymethylcytosine (5hmC) accumulate in mammalian neurons, our knowledge of its roles in terminal differentiation or as an intermediate in active DNA demethylation is incomplete. We report high-resolution mapping of DNA methylation and hydroxymethylation, chromatin accessibility, and histone marks in developing postmitotic Purkinje cells (PCs) in Mus musculus. Our data reveal new relationships between PC transcriptional and epigenetic programs, and identify a class of genes that lose both 5-methylcytosine (5mC) and 5hmC during terminal differentiation. Deletion of the 5hmC writers Tet1, Tet2, and Tet3 from postmitotic PCs prevents loss of 5mC and 5hmC in regulatory domains and gene bodies, and hinders transcriptional and epigenetic developmental transitions. Our data demonstrate that Tet-mediated active DNA demethylation occurs in vivo, and that acquisition of the precise molecular properties of adult PCs require continued oxidation of 5mC to 5hmC during the final phases of differentiation.
    Keywords:  5-hydroxymethylcytosine; DNA demethylation; TET proteins; genetics; genomics; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.66973
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