bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2023–09–10
twelve papers selected by
Connor Rogerson, University of Cambridge
  1. Symmetric inheritance of parental histones governs epigenome maintenance and embryonic stem cell identity.
  2. Symmetric inheritance of parental histones contributes to safeguarding the fate of mouse embryonic stem cells during differentiation.
  3. Ascl1 and Ngn2 convert mouse embryonic stem cells to neurons via functionally distinct paths.
  4. Epigenetic inheritance is unfaithful at intermediately methylated CpG sites.
  5. ChromGene: gene-based modeling of epigenomic data.
  6. DNA-directed termination of RNA polymerase II transcription.
  7. Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A.
  8. CRISPR-ChIP reveals selective regulation of H3K79me2 by Menin in MLL leukemia.
  9. Intra- and interchromosomal contact mapping reveals the Igh locus has extensive conformational heterogeneity and interacts with B-lineage genes.
  10. Complete human day 14 post-implantation embryo models from naïve ES cells.
  11. FOXP2 confers oncogenic effects in prostate cancer.
  12. A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.
  1. Nat Genet. 2023 Sep;55(9): 1567-1578
    Symmetric inheritance of parental histones governs epigenome maintenance and embryonic stem cell identity.
    Alice Wenger, Alva Biran, Nicolas Alcaraz, Alba Redó-Riveiro, Annika Charlotte Sell, Robert Krautz, Valentin Flury, Nazaret Reverón-Gómez, Victor Solis-Mezarino, Moritz Völker-Albert, Axel Imhof, Robin Andersson, Joshua M Brickman, Anja Groth.
      Modified parental histones are segregated symmetrically to daughter DNA strands during replication and can be inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here we show that transmission of histone-based information during DNA replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused derepression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Furthermore, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian cell differentiation.
    DOI:  https://doi.org/10.1038/s41588-023-01476-x
  2. Nat Genet. 2023 Sep;55(9): 1555-1566
    Symmetric inheritance of parental histones contributes to safeguarding the fate of mouse embryonic stem cells during differentiation.
    Qing Wen, Jiaqi Zhou, Congcong Tian, Xinran Li, Guibing Song, Yuan Gao, Yaping Sun, Chiyuan Ma, Sitong Yao, Xiaoyan Liang, Xing Kang, Nan Wang, Yuan Yao, Hongbao Wang, Xiaohuan Liang, Jialin Tang, Steven M Offer, Xiaohua Lei, Chuanhe Yu, Xiangyu Liu, Zichuan Liu, Zhiquan Wang, Haiyun Gan.
      Parental histones, the carriers of posttranslational modifications, are deposited evenly onto the replicating DNA of sister chromatids in a process dependent on the Mcm2 subunit of DNA helicase and the Pole3 subunit of leading-strand DNA polymerase. The biological significance of parental histone propagation remains unclear. Here we show that Mcm2-mutated or Pole3-deleted mouse embryonic stem cells (ESCs) display aberrant histone landscapes and impaired neural differentiation. Mutation of the Mcm2 histone-binding domain causes defects in pre-implantation development and embryonic lethality. ESCs with biased parental histone transfer exhibit increased epigenetic heterogeneity, showing altered histone variant H3.3 and H3K27me3 patterning at genomic sites regulating differentiation genes. Our results indicate that the lagging strand pattern of H3.3 leads to the redistribution of H3K27me3 in Mcm2-2A ESCs. We demonstrate that symmetric parental histone deposition to sister chromatids contributes to cellular differentiation and development.
    DOI:  https://doi.org/10.1038/s41588-023-01477-w
  3. Nat Commun. 2023 Sep 02. 14(1): 5341
    Ascl1 and Ngn2 convert mouse embryonic stem cells to neurons via functionally distinct paths.
    Gintautas Vainorius, Maria Novatchkova, Georg Michlits, Juliane Christina Baar, Cecilia Raupach, Joonsun Lee, Ramesh Yelagandula, Marius Wernig, Ulrich Elling.
      Ascl1 and Ngn2, closely related proneural transcription factors, are able to convert mouse embryonic stem cells into induced neurons. Despite their similarities, these factors elicit only partially overlapping transcriptional programs, and it remains unknown whether cells are converted via distinct mechanisms. Here we show that Ascl1 and Ngn2 induce mutually exclusive side populations by binding and activating distinct lineage drivers. Furthermore, Ascl1 rapidly dismantles the pluripotency network and installs neuronal and trophoblast cell fates, while Ngn2 generates a neural stem cell-like intermediate supported by incomplete shutdown of the pluripotency network. Using CRISPR-Cas9 knockout screening, we find that Ascl1 relies more on factors regulating pluripotency and the cell cycle, such as Tcf7l1. In the absence of Tcf7l1, Ascl1 still represses core pluripotency genes but fails to exit the cell cycle. However, overexpression of Cdkn1c induces cell cycle exit and restores the generation of neurons. These findings highlight that cell type conversion can occur through two distinct mechanistic paths, even when induced by closely related transcription factors.
    DOI:  https://doi.org/10.1038/s41467-023-40803-y
  4. Nat Commun. 2023 Sep 02. 14(1): 5336
    Epigenetic inheritance is unfaithful at intermediately methylated CpG sites.
    Amir D Hay, Noah J Kessler, Daniel Gebert, Nozomi Takahashi, Hugo Tavares, Felipe K Teixeira, Anne C Ferguson-Smith.
      DNA methylation at the CpG dinucleotide is considered a stable epigenetic mark due to its presumed long-term inheritance through clonal expansion. Here, we perform high-throughput bisulfite sequencing on clonally derived somatic cell lines to quantitatively measure methylation inheritance at the nucleotide level. We find that although DNA methylation is generally faithfully maintained at hypo- and hypermethylated sites, this is not the case at intermediately methylated CpGs. Low fidelity intermediate methylation is interspersed throughout the genome and within genes with no or low transcriptional activity, and is not coordinately maintained between neighbouring sites. We determine that the probabilistic changes that occur at intermediately methylated sites are likely due to DNMT1 rather than DNMT3A/3B activity. The observed lack of clonal inheritance at intermediately methylated sites challenges the current epigenetic inheritance model and has direct implications for both the functional relevance and general interpretability of DNA methylation as a stable epigenetic mark.
    DOI:  https://doi.org/10.1038/s41467-023-40845-2
  5. Genome Biol. 2023 Sep 07. 24(1): 203
    ChromGene: gene-based modeling of epigenomic data.
    Artur Jaroszewicz, Jason Ernst.
      Various computational approaches have been developed to annotate epigenomes on a per-position basis by modeling combinatorial and spatial patterns within epigenomic data. However, such annotations are less suitable for gene-based analyses. We present ChromGene, a method based on a mixture of learned hidden Markov models, to annotate genes based on multiple epigenomic maps across the gene body and flanks. We provide ChromGene assignments for over 100 cell and tissue types. We characterize the mixture components in terms of gene expression, constraint, and other gene annotations. The ChromGene method and annotations will provide a useful resource for gene-based epigenomic analyses.
    Keywords:  Chromatin; Epigenomics; Hidden Markov models; Histone modifications; Machine learning
    DOI:  https://doi.org/10.1186/s13059-023-03041-5
  6. Mol Cell. 2023 Aug 30. pii: S1097-2765(23)00644-5. [Epub ahead of print]
    DNA-directed termination of RNA polymerase II transcription.
    Zhong Han, George A Moore, Richard Mitter, David Lopez Martinez, Li Wan, A Barbara Dirac Svejstrup, David S Rueda, Jesper Q Svejstrup.
      RNA polymerase II (RNAPII) transcription involves initiation from a promoter, transcriptional elongation through the gene, and termination in the terminator region. In bacteria, terminators often contain specific DNA elements provoking polymerase dissociation, but RNAPII transcription termination is thought to be driven entirely by protein co-factors. We used biochemical reconstitution, single-molecule studies, and genome-wide analysis in yeast to study RNAPII termination. Transcription into natural terminators by pure RNAPII results in spontaneous termination at specific sequences containing T-tracts. Single-molecule analysis indicates that termination involves pausing without backtracking. The "torpedo" Rat1-Rai1 exonuclease (XRN2 in humans) greatly stimulates spontaneous termination but is ineffectual on other paused RNAPIIs. By contrast, elongation factor Spt4-Spt5 (DSIF) suppresses termination. Genome-wide analysis further indicates that termination occurs by transcript cleavage at the poly(A) site exposing a new 5' RNA-end that allows Rat1-Rai1 loading, which then catches up with destabilized RNAPII at specific termination sites to end transcription.
    Keywords:  CPSF73; DSIF; RNA polymerase II; Rat1; Spt5; TFIIS; XRN2; intrinsic termination site; termination; torpedo
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.007
  7. Nat Commun. 2023 Sep 05. 14(1): 5400
    Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A.
    Chen Weng, Anniya Gu, Shanshan Zhang, Leina Lu, Luxin Ke, Peidong Gao, Xiaoxiao Liu, Yuntong Wang, Peinan Hu, Dylan Plummer, Elise MacDonald, Saixian Zhang, Jiajia Xi, Sisi Lai, Konstantin Leskov, Kyle Yuan, Fulai Jin, Yan Li.
      Broad heterogeneity in pancreatic β-cell function and morphology has been widely reported. However, determining which components of this cellular heterogeneity serve a diabetes-relevant function remains challenging. Here, we integrate single-cell transcriptome, single-nuclei chromatin accessibility, and cell-type specific 3D genome profiles from human islets and identify Type II Diabetes (T2D)-associated β-cell heterogeneity at both transcriptomic and epigenomic levels. We develop a computational method to explicitly dissect the intra-donor and inter-donor heterogeneity between single β-cells, which reflect distinct mechanisms of T2D pathogenesis. Integrative transcriptomic and epigenomic analysis identifies HNF1A as a principal driver of intra-donor heterogeneity between β-cells from the same donors; HNF1A expression is also reduced in β-cells from T2D donors. Interestingly, HNF1A activity in single β-cells is significantly associated with lower Na+ currents and we nominate a HNF1A target, FXYD2, as the primary mitigator. Our study demonstrates the value of investigating disease-associated single-cell heterogeneity and provides new insights into the pathogenesis of T2D.
    DOI:  https://doi.org/10.1038/s41467-023-41228-3
  8. Nat Struct Mol Biol. 2023 Sep 07.
    CRISPR-ChIP reveals selective regulation of H3K79me2 by Menin in MLL leukemia.
    Omer Gilan, Laure Talarmain, Charles C Bell, Daniel Neville, Kathy Knezevic, Daniel T Ferguson, Marion Boudes, Yih-Chih Chan, Chen Davidovich, Enid Y N Lam, Mark A Dawson.
      Chromatin regulation involves the selective recruitment of chromatin factors to facilitate DNA repair, replication and transcription. Here we demonstrate the utility of coupling unbiased functional genomics with chromatin immunoprecipitation (CRISPR-ChIP) to identify the factors associated with active chromatin modifications in mammalian cells. Specifically, an integrated reporter containing a cis-regulatory element of interest and a single guide RNA provide a chromatinized template for a direct readout for regulators of histone modifications associated with actively transcribed genes such as H3K4me3 and H3K79me2. With CRISPR-ChIP, we identify all the nonredundant COMPASS complex members required for H3K4me3 and demonstrate that RNA polymerase II is dispensable for the maintenance of H3K4me3. As H3K79me2 has a putative oncogenic function in leukemia cells driven by MLL translocations, using CRISPR-ChIP we reveal a functional partitioning of H3K79 methylation into two distinct regulatory units: an oncogenic DOT1L complex directed by the MLL fusion protein in a Menin-dependent manner and a separate endogenous DOT1L complex, where catalytic activity is directed by MLLT10. Overall, CRISPR-ChIP provides a powerful tool for the unbiased interrogation of the mechanisms underpinning chromatin regulation.
    DOI:  https://doi.org/10.1038/s41594-023-01087-4
  9. Cell Rep. 2023 Sep 06. pii: S2211-1247(23)01085-9. [Epub ahead of print]42(9): 113074
    Intra- and interchromosomal contact mapping reveals the Igh locus has extensive conformational heterogeneity and interacts with B-lineage genes.
    Olga Mielczarek, Carolyn H Rogers, Yinxiu Zhan, Louise S Matheson, Michael J T Stubbington, Stefan Schoenfelder, Daniel J Bolland, Biola M Javierre, Steven W Wingett, Csilla Várnai, Anne Segonds-Pichon, Simon J Conn, Felix Krueger, Simon Andrews, Peter Fraser, Luca Giorgetti, Anne E Corcoran.
      To produce a diverse antibody repertoire, immunoglobulin heavy-chain (Igh) loci undergo large-scale alterations in structure to facilitate juxtaposition and recombination of spatially separated variable (VH), diversity (DH), and joining (JH) genes. These chromosomal alterations are poorly understood. Uncovering their patterns shows how chromosome dynamics underpins antibody diversity. Using tiled Capture Hi-C, we produce a comprehensive map of chromatin interactions throughout the 2.8-Mb Igh locus in progenitor B cells. We find that the Igh locus folds into semi-rigid subdomains and undergoes flexible looping of the VH genes to its 3' end, reconciling two views of locus organization. Deconvolution of single Igh locus conformations using polymer simulations identifies thousands of different structures. This heterogeneity may underpin the diversity of V(D)J recombination events. All three immunoglobulin loci also participate in a highly specific, developmentally regulated network of interchromosomal interactions with genes encoding B cell-lineage factors. This suggests a model of interchromosomal coordination of B cell development.
    Keywords:  3D immunoglobulin structure; CP: Immunology; Capture Hi-C; genome organization; immunoglobin locus; interchromosomal; polymer modeling
    DOI:  https://doi.org/10.1016/j.celrep.2023.113074
  10. Nature. 2023 Sep 06.
    Complete human day 14 post-implantation embryo models from naïve ES cells.
    Bernardo Oldak, Emilie Wildschutz, Vladyslav Bondarenko, Mehmet-Yunus Comar, Cheng Zhao, Alejandro Aguilera-Castrejon, Shadi Tarazi, Sergey Viukov, Thi Xuan Ai Pham, Shahd Ashouokhi, Dmitry Lokshtanov, Francesco Roncato, Eitan Ariel, Max Rose, Nir Livnat, Tom Shani, Carine Joubran, Roni Cohen, Yoseph Addadi, Muriel Chemla, Merav Kedmi, Hadas Keren-Shaul, Vincent Pasque, Sophie Petropoulos, Fredrik Lanner, Noa Novershtern, Jacob H Hanna.
      The ability to study human post-implantation development remains limited due to ethical and technical challenges associated with intrauterine development after implantation1. Embryo-like models with spatially organized morphogenesis of all defining embryonic and extra-embryonic tissues of the post-implantation human conceptus (i.e., embryonic disk, bilaminar disk, yolk- and chorionic sacs, surrounding trophoblasts) remain lacking2. Mouse naïve embryonic stem cells (ESCs) have recently been shown to give rise to embryonic and extra-embryonic stem cells capable of self-assembling into post-gastrulation mouse Structured Stem cell-based Embryo Models with spatially organized morphogenesis (SEMs)3. Here, we extend these findings to humans, while using only genetically unmodified human naïve ESCs (in HENSM conditions)4. Such human fully integrated SEMs recapitulate the organization of nearly all known lineages and compartments of post-implantation human embryos including epiblast, hypoblast, extra-embryonic mesoderm, and trophoblast surrounding the latter layers. These human complete SEMs demonstrated developmental growth dynamics that resemble key hallmarks of post-implantation stage embryogenesis up to 13-14 days post-fertilization (dpf) (Carnegie stage 6a). This includes embryonic disk and bilaminar disk formation, epiblast lumenogenesis, polarized amniogenesis, anterior-posterior symmetry breaking, PGC specification, polarized yolk sac with visceral and parietal endoderm, extra-embryonic mesoderm expansion that defines a chorionic cavity and a connecting stalk, a trophoblast surrounding compartment demonstrating syncytium and lacunae formation. This SEM platform may enable the experimental interrogation of previously inaccessible windows of human early post-implantation up to peri-gastrulation development.
    DOI:  https://doi.org/10.1038/s41586-023-06604-5
  11. Elife. 2023 Sep 05. pii: e81258. [Epub ahead of print]12
    FOXP2 confers oncogenic effects in prostate cancer.
    Xiaoquan Zhu, Chao Chen, Dong Wei, Yong Xu, Siying Liang, Wenlong Jia, Jian Li, Yanchun Qu, Jianpo Zhai, Yaoguang Zhang, Pengjie Wu, Qiang Hao, Linlin Zhang, Wei Zhang, Xinyu Yang, Lin Pan, Ruomei Qi, Yao Li, Feiliang Wang, Rui Yi, Ze Yang, Jianye Wang, Yanyang Zhao.
      Identification oncogenes is fundamental to revealing the molecular basis of cancer. Here, we found that FOXP2 is overexpressed in human prostate cancer cells and prostate tumors, but its expression is absent in normal prostate epithelial cells and low in benign prostatic hyperplasia. FOXP2 is a FOX transcription factor family member and tightly associated with vocal development. To date, little is known regarding the link of FOXP2 to prostate cancer. We observed that high FOXP2 expression and frequent amplification are significantly associated with high Gleason score. Ectopic expression of FOXP2 induces malignant transformation of mouse NIH3T3 fibroblasts and human prostate epithelial cell RWPE-1. Conversely, FOXP2 knockdown suppresses the proliferation of prostate cancer cells. Transgenic overexpression of FOXP2 in the mouse prostate causes prostatic intraepithelial neoplasia. Overexpression of FOXP2 aberrantly activates oncogenic MET signalling and inhibition of MET signalling effectively reverts the FOXP2-induced oncogenic phenotype. CUT&Tag assay identified FOXP2-binding sites located in MET and its associated gene HGF. Additionally, the novel recurrent FOXP2-CPED1 fusion identified in prostate tumors results in high expression of truncated FOXP2, which exhibit a similar capacity for malignant transformation. Together, our data indicate that FOXP2 is involved in tumorigenicity of prostate.
    Keywords:  biochemistry; cancer biology; chemical biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.81258
  12. Nat Commun. 2023 Sep 06. 14(1): 5195
    A super-enhancer-regulated RNA-binding protein cascade drives pancreatic cancer.
    Corina E Antal, Tae Gyu Oh, Stefan Aigner, En-Ching Luo, Brian A Yee, Tania Campos, Hervé Tiriac, Katherine L Rothamel, Zhang Cheng, Henry Jiao, Allen Wang, Nasun Hah, Elizabeth Lenkiewicz, Jan C Lumibao, Morgan L Truitt, Gabriela Estepa, Ester Banayo, Senada Bashi, Edgar Esparza, Ruben M Munoz, Jolene K Diedrich, Nicole M Sodir, Jasmine R Mueller, Cory R Fraser, Erkut Borazanci, David Propper, Daniel D Von Hoff, Christopher Liddle, Ruth T Yu, Annette R Atkins, Haiyong Han, Andrew M Lowy, Michael T Barrett, Dannielle D Engle, Gerard I Evan, Gene W Yeo, Michael Downes, Ronald M Evans.
      Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.
    DOI:  https://doi.org/10.1038/s41467-023-40798-6
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