bims-crepig Biomed News
on Chromatin regulation and epigenetics in cell fate and cancer
Issue of 2023–02–19
sixteen papers selected by
Connor Rogerson, University of Cambridge
  1. H3.3 contributes to chromatin accessibility and transcription factor binding at promoter-proximal regulatory elements in embryonic stem cells.
  2. The SET oncoprotein promotes estrogen-induced transcription by facilitating establishment of active chromatin.
  3. Increased chromatin accessibility promotes the evolution of a transcriptional silencer in Drosophila.
  4. Single-cell-resolved dynamics of chromatin architecture delineate cell and regulatory states in zebrafish embryos.
  5. Multiscale 3D genome reorganization during skeletal muscle stem cell lineage progression and aging.
  6. Atlas-scale single-cell chromatin accessibility using nanowell-based combinatorial indexing.
  7. Synthetic analysis of chromatin tracing and live-cell imaging indicates pervasive spatial coupling between genes.
  8. De novo human brain enhancers created by single-nucleotide mutations.
  9. The HP1α protein is mandatory to repress the circadian clock and its output genes during the 12 h period of transcriptional repression.
  10. GLIS3 regulates transcription of thyroid hormone biosynthetic genes in coordination with other thyroid transcription factors.
  11. Biotinylated Tn5 Transposase-mediated CUT&Tag Efficiently Profiles Transcription Factor-DNA Interactions in Plants.
  12. Long range inter-chromosomal interaction of Oct4 distal enhancer loci regulates ESCs pluripotency.
  13. The ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome.
  14. Mitochondrial single-cell ATAC-seq for high-throughput multi-omic detection of mitochondrial genotypes and chromatin accessibility.
  15. Transcription factor binding sites are frequently under accelerated evolution in primates.
  16. Single cell epigenomic and transcriptomic analysis uncovers potential transcription factors regulating mitotic/meiotic switch.
  1. Genome Biol. 2023 Feb 13. 24(1): 25
    H3.3 contributes to chromatin accessibility and transcription factor binding at promoter-proximal regulatory elements in embryonic stem cells.
    Amanuel Tafessu, Ryan O'Hara, Sara Martire, Altair L Dube, Purbita Saha, Vincent U Gant, Laura A Banaszynski.
       BACKGROUND: The histone variant H3.3 is enriched at active regulatory elements such as promoters and enhancers in mammalian genomes. These regions are highly accessible, creating an environment that is permissive to transcription factor binding and the recruitment of transcriptional coactivators that establish a unique chromatin post-translational landscape. How H3.3 contributes to the establishment and function of chromatin states at these regions is poorly understood.
    RESULTS: We perform genomic analyses of features associated with active promoter chromatin in mouse embryonic stem cells (ESCs) and find evidence of subtle yet widespread promoter dysregulation in the absence of H3.3. Loss of H3.3 results in reduced chromatin accessibility and transcription factor (TF) binding at promoters of expressed genes in ESCs. Likewise, enrichment of the transcriptional coactivator p300 and downstream histone H3 acetylation at lysine 27 (H3K27ac) is reduced at promoters in the absence of H3.3, along with reduced enrichment of the acetyl lysine reader BRD4. Despite the observed chromatin dysregulation, H3.3 KO ESCs maintain transcription from ESC-specific genes. However, upon undirected differentiation, H3.3 KO cells retain footprinting of ESC-specific TF motifs and fail to generate footprints of lineage-specific TF motifs, in line with their diminished capacity to differentiate.
    CONCLUSIONS: H3.3 facilitates DNA accessibility, transcription factor binding, and histone post-translational modification at active promoters. While H3.3 is not required for maintaining transcription in ESCs, it does promote de novo transcription factor binding which may contribute to the dysregulation of cellular differentiation in the absence of H3.3.
    Keywords:  Chromatin accessibility; Differentiation; Embryonic stem cells; Histone variants; Transcription factor binding
    DOI:  https://doi.org/10.1186/s13059-023-02867-3
  2. Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2206878120
    The SET oncoprotein promotes estrogen-induced transcription by facilitating establishment of active chromatin.
    Changying Guo, Karla F Meza-Sosa, David Valle-Garcia, Guomeng Zhao, Kun Gao, Liting Yu, Hongying Zhang, Yeqing Chen, Liang Sun, Shira Rockowitz, Shouyu Wang, Sheng Jiang, Judy Lieberman.
      SET is a multifunctional histone-binding oncoprotein that regulates transcription by an unclear mechanism. Here we show that SET enhances estrogen-dependent transcription. SET knockdown abrogates transcription of estrogen-responsive genes and their enhancer RNAs. In response to 17β-estradiol (E2), SET binds to the estrogen receptor α (ERα) and is recruited to ERα-bound enhancers and promoters at estrogen response elements (EREs). SET functions as a histone H2 chaperone that dynamically associates with H2A.Z via its acidic C-terminal domain and promotes H2A.Z incorporation, ERα, MLL1, and KDM3A loading and modulates histone methylation at EREs. SET depletion diminishes recruitment of condensin complexes to EREs and impairs E2-dependent enhancer-promoter looping. Thus, SET boosts E2-induced gene expression by establishing an active chromatin structure at ERα-bound enhancers and promoters, which is essential for transcriptional activation.
    Keywords:  SET; breast cancer; estrogen; histone chaperone; transcriptional activation
    DOI:  https://doi.org/10.1073/pnas.2206878120
  3. Sci Adv. 2023 Feb 17. 9(7): eade6529
    Increased chromatin accessibility promotes the evolution of a transcriptional silencer in Drosophila.
    Liucong Ling, Bettina Mühling, Rita Jaenichen, Nicolas Gompel.
      The loss of discrete morphological traits, the most common evolutionary transition, is typically driven by changes in developmental gene expression. Mutations accumulating in regulatory elements of these genes can disrupt DNA binding sites for transcription factors patterning their spatial expression, or delete entire enhancers. Regulatory elements, however, may be silenced through changes in chromatin accessibility or the emergence of repressive elements. Here, we show that increased chromatin accessibility at the gene yellow, combined with the gain of a repressor site, underlies the loss of a wing spot pigmentation pattern in a Drosophila species. The gain of accessibility of this repressive element is regulated by E93, a transcription factor governing the progress of metamorphosis. This convoluted evolutionary scenario contrasts with the parsimonious mutational paths generally envisioned and often documented for morphological losses. It illustrates how evolutionary changes in chromatin accessibility may directly contribute to morphological diversification.
    DOI:  https://doi.org/10.1126/sciadv.ade6529
  4. Cell Genom. 2022 Jan 12. 2(1): 100083
    Single-cell-resolved dynamics of chromatin architecture delineate cell and regulatory states in zebrafish embryos.
    Alison C McGarvey, Wolfgang Kopp, Dubravka Vučićević, Kenny Mattonet, Rieke Kempfer, Antje Hirsekorn, Ilija Bilić, Marine Gil, Alexandra Trinks, Anne Margarete Merks, Daniela Panáková, Ana Pombo, Altuna Akalin, Jan Philipp Junker, Didier Y R Stainier, David Garfield, Uwe Ohler, Scott Allen Lacadie.
      DNA accessibility of cis-regulatory elements (CREs) dictates transcriptional activity and drives cell differentiation during development. While many genes regulating embryonic development have been identified, the underlying CRE dynamics controlling their expression remain largely uncharacterized. To address this, we produced a multimodal resource and genomic regulatory map for the zebrafish community, which integrates single-cell combinatorial indexing assay for transposase-accessible chromatin with high-throughput sequencing (sci-ATAC-seq) with bulk histone PTMs and Hi-C data to achieve a genome-wide classification of the regulatory architecture determining transcriptional activity in the 24-h post-fertilization (hpf) embryo. We characterized the genome-wide chromatin architecture at bulk and single-cell resolution, applying sci-ATAC-seq on whole 24-hpf stage zebrafish embryos, generating accessibility profiles for ∼23,000 single nuclei. We developed a genome segmentation method, ScregSeg (single-cell regulatory landscape segmentation), for defining regulatory programs, and candidate CREs, specific to one or more cell types. We integrated the ScregSeg output with bulk measurements for histone post-translational modifications and 3D genome organization and identified new regulatory principles between chromatin modalities prevalent during zebrafish development. Sci-ATAC-seq profiling of npas4l/cloche mutant embryos identified novel cellular roles for this hematovascular transcriptional master regulator and suggests an intricate mechanism regulating its expression. Our work defines regulatory architecture and principles in the zebrafish embryo and establishes a resource of cell-type-specific genome-wide regulatory annotations and candidate CREs, providing a valuable open resource for genomics, developmental, molecular, and computational biology.
    Keywords:  Hi-C; chromatin; cis regulatory element; enhancer; npas4l; promoter; single-cell ATAC-seq; zebrafish
    DOI:  https://doi.org/10.1016/j.xgen.2021.100083
  5. Sci Adv. 2023 Feb 17. 9(7): eabo1360
    Multiscale 3D genome reorganization during skeletal muscle stem cell lineage progression and aging.
    Yu Zhao, Yingzhe Ding, Liangqiang He, Qin Zhou, Xiaona Chen, Yuying Li, Maria Vittoria Alfonsi, Zhenguo Wu, Hao Sun, Huating Wang.
      Little is known about three-dimensional (3D) genome organization in skeletal muscle stem cells [also called satellite cells (SCs)]. Here, we comprehensively map the 3D genome topology reorganization during mouse SC lineage progression. Specifically, rewiring at the compartment level is most pronounced when SCs become activated. Marked loss in topologically associating domain (TAD) border insulation and chromatin looping also occurs during early activation process. Meanwhile, TADs can form TAD clusters and super-enhancer-containing TAD clusters orchestrate stage-specific gene expression. Furthermore, we uncover that transcription factor PAX7 is pivotal in enhancer-promoter (E-P) loop formation. We also identify cis-regulatory elements that are crucial for local chromatin organization at Pax7 locus and Pax7 expression. Lastly, we unveil that geriatric SC displays a prominent gain in long-range contacts and loss of TAD border insulation. Together, our results uncover that 3D chromatin extensively reorganizes at multiple architectural levels and underpins the transcriptome remodeling during SC lineage development and SC aging.
    DOI:  https://doi.org/10.1126/sciadv.abo1360
  6. Genome Res. 2023 Feb 15. pii: gr.276655.122. [Epub ahead of print]
    Atlas-scale single-cell chromatin accessibility using nanowell-based combinatorial indexing.
    Brendan L O'Connell, Ruth V Nichols, Dmitry Pokholok, Jerushah Thomas, Sonia N Acharya, Andrew Nishida, Casey A Thornton, Marissa Co, Andrew J Fields, Frank J Steemers, Andrew C Adey.
      Here we present advancements in single-cell combinatorial indexed ATAC-seq (sciATAC) to measure chromatin accessibility that leverage nanowell chips to achieve atlas-scale cell throughput (>105) at low cost. The platform leverages the core of the sciATAC workflow where multiple indexed tagmentation reactions are performed, followed by pooling and distribution to a second set of reaction wells for PCR-based indexing. In this work, we instead leverage a chip containing 5,184 nanowells as the PCR stage of indexing, enabling a 52-fold improvement in scale and reduction in per-cell preparation costs. We detail three variants that balance cell throughput and depth of coverage and apply these methods to banked mouse brain tissue, producing maps of cell types as well as neuronal subtypes that includes integration with exiting scATAC and scRNA-seq datasets. Our optimized workflow achieves a high fraction of reads that fall within called peaks (>80%) and low cell doublet rates. The high cell coverage technique produces high unique reads per cell, while retaining high enrichment for open chromatin regions, enabling the assessment of >70,000 unique accessible on average for each cell profiled. When compared to current methods in the field, our technique provides similar or superior per-cell information with very low levels of cell-to-cell crosstalk, and achieves this at a cost point much lower than existing assays.
    DOI:  https://doi.org/10.1101/gr.276655.122
  7. Elife. 2023 Feb 15. pii: e81861. [Epub ahead of print]12
    Synthetic analysis of chromatin tracing and live-cell imaging indicates pervasive spatial coupling between genes.
    Christopher H Bohrer, Daniel R Larson.
      The role of the spatial organization of chromosomes in directing transcription remains an outstanding question in gene regulation. Here, we analyze two recent single-cell imaging methodologies applied across hundreds of genes to systematically analyze the contribution of chromosome conformation to transcriptional regulation. Those methodologies are: 1) single-cell chromatin tracing with super-resolution imaging in fixed cells; 2) high throughput labeling and imaging of nascent RNA in living cells. Specifically, we determine the contribution of physical distance to the coordination of transcriptional bursts. We find that individual genes adopt a constrained conformation and reposition toward the centroid of the surrounding chromatin upon activation. Leveraging the variability in distance inherent in single-cell imaging, we show that physical distance - but not genomic distance - between genes on individual chromosomes is the major factor driving co-bursting. By combining this analysis with live-cell imaging, we arrive at a corrected transcriptional correlation of ϕ ≈0.3 for genes separated by < 400 nm. We propose that this surprisingly large correlation represents a physical property of human chromosomes and establishes a benchmark for future experimental studies.
    Keywords:  chromosomes; computational biology; gene expression; none; systems biology
    DOI:  https://doi.org/10.7554/eLife.81861
  8. Sci Adv. 2023 Feb 15. 9(7): eadd2911
    De novo human brain enhancers created by single-nucleotide mutations.
    Shan Li, Sridhar Hannenhalli, Ivan Ovcharenko.
      Advanced human cognition is attributed to increased neocortex size and complexity, but the underlying evolutionary and regulatory mechanisms are largely unknown. Using human and macaque embryonic neocortical H3K27ac data coupled with a deep learning model of enhancers, we identified ~4000 enhancer gains in humans, which, per our model, can often be attributed to single-nucleotide essential mutations. Our analyses suggest that functional gains in embryonic brain development are associated with de novo enhancers whose putative target genes exhibit increased expression in progenitor cells and interneurons and partake in critical neural developmental processes. Essential mutations alter enhancer activity through altered binding of key transcription factors (TFs) of embryonic neocortex, including ISL1, POU3F2, PITX1/2, and several SOX TFs, and are associated with central nervous system disorders. Overall, our results suggest that essential mutations lead to gain of embryonic neocortex enhancers, which orchestrate expression of genes involved in critical developmental processes associated with human cognition.
    DOI:  https://doi.org/10.1126/sciadv.add2911
  9. Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2213075120
    The HP1α protein is mandatory to repress the circadian clock and its output genes during the 12 h period of transcriptional repression.
    Nisha Misra, Manohar Damara, Pierre Chambon.
      The transcriptional repressions driven by the circadian core clock repressors RevErbα, E4BP4, and CRY1/PER1 involve feedback loops which are mandatory for generating the circadian rhythms. These repressors are known to bind to cognate DNA binding sites, but how their circadian bindings trigger the cascade of events leading to these repressions remain to be elucidated. Through molecular and genetic analyses, we now demonstrate that the chromatin protein HP1α plays a key role in these transcriptional repressions of both the circadian clock (CC) genes and their cognate output genes (CCGs). We show that these CC repressors recruit the HP1α protein downstream from a repressive cascade, and that this recruitment is mandatory for the maintenance of both the CC integrity and the expression of the circadian genes. We further show that the presence of HP1α is critical for both the repressor-induced chromatin compaction and the generation of "transcriptionally repressed biomolecular hydrophobic condensates" and demonstrates that HP1α is mandatory within the CC output genes for both the recruitment of DNA methylating enzymes on the intronic deoxyCpG islands and their subsequent methylation.
    Keywords:  circadian DNA methylation–demethylation; circadian clock; circadian transcription; circadian transcriptional repression; intronic deoxyCpG-Islands
    DOI:  https://doi.org/10.1073/pnas.2213075120
  10. Cell Biosci. 2023 Feb 15. 13(1): 32
    GLIS3 regulates transcription of thyroid hormone biosynthetic genes in coordination with other thyroid transcription factors.
    Hong Soon Kang, Sara A Grimm, Raja Jothi, Pilar Santisteban, Anton M Jetten.
       BACKGROUND: Loss of the transcription factor GLI-Similar 3 (GLIS3) function causes congenital hypothyroidism (CH) in both humans and mice due to decreased expression of several thyroid hormone (TH) biosynthetic genes in thyroid follicular cells. Whether and to what extent, GLIS3 regulates thyroid gene transcription in coordination with other thyroid transcriptional factors (TFs), such as PAX8, NKX2.1 and FOXE1, is poorly understood.
    METHODS: PAX8, NKX2.1, and FOXE1 ChIP-Seq analysis with mouse thyroid glands and rat thyrocyte PCCl3 cells was performed and compared to that of GLIS3 to analyze the co-regulation of gene transcription in thyroid follicular cells by these TFs.
    RESULTS: Analysis of the PAX8, NKX2.1, and FOXE1 cistromes identified extensive overlaps between these TF binding loci and those of GLIS3 indicating that GLIS3 shares many of the same regulatory regions with PAX8, NKX2.1, and FOXE1, particularly in genes associated with TH biosynthesis, induced by thyroid stimulating hormone (TSH), and suppressed in Glis3KO thyroid glands, including Slc5a5 (Nis), Slc26a4, Cdh16, and Adm2. ChIP-QPCR analysis showed that loss of GLIS3 did not significantly affect PAX8 or NKX2.1 binding and did not cause major alterations in H3K4me3 and H3K27me3 epigenetic signals.
    CONCLUSIONS: Our study indicates that GLIS3 regulates transcription of TH biosynthetic and TSH-inducible genes in thyroid follicular cells in coordination with PAX8, NKX2.1, and FOXE1 by binding within the same regulatory hub. GLIS3 does not cause major changes in chromatin structure at these common regulatory regions. GLIS3 may induce transcriptional activation by enhancing the interaction of these regulatory regions with other enhancers and/or RNA Polymerase II (Pol II) complexes.
    Keywords:  FOXE1; GLIS3; Gene transcription; NIS; NKX2.1; PAX8; PCCl3; TSH; Thyroid follicular cells; Thyroid hormone biosynthesis
    DOI:  https://doi.org/10.1186/s13578-023-00979-8
  11. Plant Biotechnol J. 2023 Feb 14.
    Biotinylated Tn5 Transposase-mediated CUT&Tag Efficiently Profiles Transcription Factor-DNA Interactions in Plants.
    Xiao-Yuan Tao, Xue-Ying Guan, Gao-Jie Hong, Yu-Qing He, Su-Juan Li, Shou-Li Feng, Jian Wang, Guang Chen, Fei Xu, Jia-Wei Wang, Sheng-Chun Xu.
      In contrast to CUT&Tag approaches for profiling bulk histone modifications, current CUT&Tag methods for analyzing specific transcription factor (TF)-DNA interactions remain technically challenging due to TFs having relatively low abundance. Moreover, an efficient CUT&Tag strategy for plant TFs is not yet available. Here, we first applied biotinylated Tn5 transposase-mediated CUT&Tag (B-CUT&Tag) to produce high-quality libraries for interrogating TF-DNA interactions. B-CUT&Tag combines streptavidin-biotin-based DNA purification with routine CUT&Tag, optimizing the removal of large amounts of intact chromatin not targeted by specific TFs. The biotinylated chromatin fragments are then purified for construction of deep sequencing libraries or qPCR analysis. We applied B-CUT&Tag to probe genome-wide DNA targets of Squamosa promoter-binding-like protein 9 (SPL9), a well-established TF in Arabidopsis; the resulting profiles were efficient and consistent in demonstrating its well-established target genes in juvenile-adult transition/flowering, trichome development, flavonoid biosynthesis, wax synthesis, and branching. Interestingly, our results indicate functions of AtSPL9 in modulating growth-defense trade-offs. In addition, we established a method for applying qPCR after CUT&Tag (B-CUT&Tag-qPCR) and successfully validated the binding of SPL9 in Arabidopsis and PHR2 in rice. Our study thus provides a convenient and highly efficient CUT&Tag strategy for profiling TF-chromatin interactions that is widely applicable to the annotation of cis-regulatory elements for crop improvement.
    Keywords:  Arabidopsis; AtSPL9; B-CUT&Tag; B-CUT&Tag-qPCR; B-CUT&Tag-seq; OsPHR2; Transcription factor; defense; flowering; rice
    DOI:  https://doi.org/10.1111/pbi.14029
  12. Cell Death Discov. 2023 Feb 13. 9(1): 61
    Long range inter-chromosomal interaction of Oct4 distal enhancer loci regulates ESCs pluripotency.
    Byoung-San Moon, David Huang, Fan Gao, Mingyang Cai, Guochang Lyu, Lei Zhang, Jun Chen, Wange Lu.
      Nuclear architecture underlies the transcriptional programs within the cell to establish cell identity. As previously demonstrated, long-range chromatin interactions of the Oct4 distal enhancer (DE) are correlated with active transcription in naïve state embryonic stem cells. Here, we identify and characterize extreme long-range interactions of the Oct4 DE through a novel CRISPR labeling technique we developed and chromosome conformation capture to identify lethal giant larvae 2 (Llgl2) and growth factor receptor-bound protein 7 (Grb7) as putative functional interacting target genes in different chromosomes. We show that the Oct4 DE directly regulates expression of Llgl2 and Grb7 in addition to Oct4. Expression of Llgl2 and Grb7 closely correlates with the pluripotent state, where knock down of either result in loss of pluripotency, and overexpression enhances somatic cell reprogramming. We demonstrated that biologically important interactions of the Oct4 DE can occur at extreme distances that are necessary for the maintenance of the pluripotent state.
    DOI:  https://doi.org/10.1038/s41420-023-01363-8
  13. Nat Commun. 2023 Feb 16. 14(1): 887
    The ULK3 kinase is a determinant of keratinocyte self-renewal and tumorigenesis targeting the arginine methylome.
    Sandro Goruppi, Andrea Clocchiatti, Giulia Bottoni, Emery Di Cicco, Min Ma, Beatrice Tassone, Victor Neel, Shadhmer Demehri, Christian Simon, G Paolo Dotto.
      Epigenetic mechanisms oversee epidermal homeostasis and oncogenesis. The identification of kinases controlling these processes has direct therapeutic implications. We show that ULK3 is a nuclear kinase with elevated expression levels in squamous cell carcinomas (SCCs) arising in multiple body sites, including skin and Head/Neck. ULK3 loss by gene silencing or deletion reduces proliferation and clonogenicity of human keratinocytes and SCC-derived cells and affects transcription impinging on stem cell-related and metabolism programs. Mechanistically, ULK3 directly binds and regulates the activity of two histone arginine methyltransferases, PRMT1 and PRMT5 (PRMT1/5), with ULK3 loss compromising PRMT1/5 chromatin association to specific genes and overall methylation of histone H4, a shared target of these enzymes. These findings are of translational significance, as downmodulating ULK3 by RNA interference or locked antisense nucleic acids (LNAs) blunts the proliferation and tumorigenic potential of SCC cells and promotes differentiation in two orthotopic models of skin cancer.
    DOI:  https://doi.org/10.1038/s41467-023-36410-6
  14. Nat Protoc. 2023 Feb 15.
    Mitochondrial single-cell ATAC-seq for high-throughput multi-omic detection of mitochondrial genotypes and chromatin accessibility.
    Caleb A Lareau, Vincent Liu, Christoph Muus, Samantha D Praktiknjo, Lena Nitsch, Pauline Kautz, Katalin Sandor, Yajie Yin, Jacob C Gutierrez, Karin Pelka, Ansuman T Satpathy, Aviv Regev, Vijay G Sankaran, Leif S Ludwig.
      Natural sequence variation within mitochondrial DNA (mtDNA) contributes to human phenotypes and may serve as natural genetic markers in human cells for clonal and lineage tracing. We recently developed a single-cell multi-omic approach, called 'mitochondrial single-cell assay for transposase-accessible chromatin with sequencing' (mtscATAC-seq), enabling concomitant high-throughput mtDNA genotyping and accessible chromatin profiling. Specifically, our technique allows the mitochondrial genome-wide inference of mtDNA variant heteroplasmy along with information on cell state and accessible chromatin variation in individual cells. Leveraging somatic mtDNA mutations, our method further enables inference of clonal relationships among native ex vivo-derived human cells not amenable to genetic engineering-based clonal tracing approaches. Here, we provide a step-by-step protocol for the use of mtscATAC-seq, including various cell-processing and flow cytometry workflows, by using primary hematopoietic cells, subsequent single-cell genomic library preparation and sequencing that collectively take ~3-4 days to complete. We discuss experimental and computational data quality control metrics and considerations for the extension to other mammalian tissues. Overall, mtscATAC-seq provides a broadly applicable platform to map clonal relationships between cells in human tissues, investigate fundamental aspects of mitochondrial genetics and enable additional modes of multi-omic discovery.
    DOI:  https://doi.org/10.1038/s41596-022-00795-3
  15. Nat Commun. 2023 Feb 11. 14(1): 783
    Transcription factor binding sites are frequently under accelerated evolution in primates.
    Xinru Zhang, Bohao Fang, Yi-Fei Huang.
      Recent comparative genomic studies have identified many human accelerated elements (HARs) with elevated substitution rates in the human lineage. However, it remains unknown to what extent transcription factor binding sites (TFBSs) are under accelerated evolution in humans and other primates. Here, we introduce two pooling-based phylogenetic methods with dramatically enhanced sensitivity to examine accelerated evolution in TFBSs. Using these new methods, we show that more than 6000 TFBSs annotated in the human genome have experienced accelerated evolution in Hominini, apes, and Old World monkeys. Although these TFBSs individually show relatively weak signals of accelerated evolution, they collectively are more abundant than HARs. Also, we show that accelerated evolution in Pol III binding sites may be driven by lineage-specific positive selection, whereas accelerated evolution in other TFBSs might be driven by nonadaptive evolutionary forces. Finally, the accelerated TFBSs are enriched around developmental genes, suggesting that accelerated evolution in TFBSs may drive the divergence of developmental processes between primates.
    DOI:  https://doi.org/10.1038/s41467-023-36421-3
  16. Cell Death Dis. 2023 Feb 17. 14(2): 134
    Single cell epigenomic and transcriptomic analysis uncovers potential transcription factors regulating mitotic/meiotic switch.
    Fa-Li Zhang, Yan-Qin Feng, Jing-Ya Wang, Ke-Xin Zhu, Lu Wang, Jia-Mao Yan, Xiu-Xiu Li, Jun-Jie Wang, Wei Ge, Massimo De Felici, Wei Shen.
      In order to reveal the complex mechanism governing the mitotic/meiotic switch in female germ cells at epigenomic and genomic levels, we examined the chromatin accessibility (scATAC-seq) and the transcriptional dynamics (scRNA-seq) in germ cells of mouse embryonic ovary between E11.5 to 13.5 at single-cell resolution. Adopting a strict transcription factors (TFs) screening framework that makes it easier to understand the single-cell chromatin signature and a TF interaction algorithm that integrates the transcript levels, chromatin accessibility, and motif scores, we identified 14 TFs potentially regulating the mitotic/meiotic switch, including TCFL5, E2F1, E2F2, E2F6, E2F8, BATF3, SP1, FOS, FOXN3, VEZF1, GBX2, CEBPG, JUND, and TFDP1. Focusing on TCFL5, we constructed Tcfl5+/- mice which showed significantly reduced fertility and found that decreasing TCFL5 expression in cultured E12.5 ovaries by RNAi impaired meiotic progression from leptotene to zygotene. Bioinformatics analysis of published results of the embryonic germ cell transcriptome and the finding that in these cells central meiotic genes (Stra8, Tcfl5, Sycp3, and E2f2) possess open chromatin status already at the mitotic stage together with other features of TCFL5 (potential capability to interact with core TFs and activate meiotic genes, its progressive activation after preleptotene, binding sites in the promoter region of E2f2 and Sycp3), indicated extensive amplification of transcriptional programs associated to mitotic/meiotic switch with an important contribution of TCFL5. We conclude that the identified TFs, are involved in various stages of the mitotic/meiotic switch in female germ cells, TCFL5 primarily in meiotic progression. Further investigation on these factors might give a significant contribution to unravel the molecular mechanisms of this fundamental process of oogenesis and provide clues about pathologies in women such as primary ovarian insufficiency (POI) due at least in part to meiotic defects.
    DOI:  https://doi.org/10.1038/s41419-023-05671-w
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