Showing papers in "Genes & Development in 2022"
TL;DR: In this review, Ridge et al. discuss the essential functions of vimentin IFs revealed from studies of Vim−/− mice and cells derived from them.
Abstract: In this review, Ridge et al. discuss the essential functions of vimentin IFs revealed from studies of Vim−/− mice and cells derived from them.
36 citations
TL;DR: The major classes of DNA repair and damage signaling defects in cancer, the genomic instability that they give rise to, and therapeutic strategies to exploit the resulting vulnerabilities are reviewed.
Abstract: In this review, Hopkins et al. review the major classes of DNA repair and damage signaling defects in cancer, the genomic instability that they give rise to, and therapeutic strategies to exploit the resulting vulnerabilities. They also discuss the impacts of DNA repair defects on both targeted therapy and immunotherapy, and highlight emerging principles for targeting DNA repair defects in cancer therapy.
23 citations
TL;DR: In this study, Boreikaite et al. reconstituted specific and efficient 3′ endonuclease activity of human CPSF with purified proteins, which required the seven-subunit CPSF as well as three additional protein factors: cleavage stimulatory factor, cleavage factor IIm, and the multidomain protein RBBP6.
Abstract: In this study, Boreikaite et al. reconstituted specific and efficient 3′ endonuclease activity of human CPSF with purified proteins. This required the seven-subunit CPSF as well as three additional protein factors: cleavage stimulatory factor (CStF), cleavage factor IIm (CFIIm), and, importantly, the multidomain protein RBBP6.
21 citations
TL;DR: Here, Schmidt et al. reconstituted the endonucleolytic cleavage of an extended precursor followed by the addition of a poly(A) tail reaction from overproduced and purified proteins, and provide a minimal list of 14 polypeptides that are essential and two that are stimulatory for RNA processing.
Abstract: Here, Schmidt et al. reconstituted the endonucleolytic cleavage of an extended precursor followed by the addition of a poly(A) tail reaction from overproduced and purified proteins, and provide a minimal list of 14 polypeptides that are essential and two that are stimulatory for RNA processing.
20 citations
TL;DR: In this article , the authors synthesize recent discoveries on the mechanisms of small cell lung cancer plasticity and how these processes may impinge on antitumor immunity and reveal novel targets for alternative immunotherapeutic approaches.
Abstract: Small cell lung cancer (SCLC) is a rapidly growing, highly metastatic, and relatively immune-cold lung cancer subtype. Historically viewed in the laboratory and clinic as a single disease, new discoveries suggest that SCLC comprises multiple molecular subsets. Expression of MYC family members and lineage-related transcription factors ASCL1, NEUROD1, and POU2F3 (and, in some studies, YAP1) define unique molecular states that have been associated with distinct responses to a variety of therapies. However, SCLC tumors exhibit a high degree of intratumoral heterogeneity, with recent studies suggesting the existence of tumor cell plasticity and phenotypic switching between subtype states. While SCLC plasticity is correlated with, and likely drives, therapeutic resistance, the mechanisms underlying this plasticity are still largely unknown. Subtype states are also associated with immune-related gene expression, which likely impacts response to immune checkpoint blockade and may reveal novel targets for alternative immunotherapeutic approaches. In this review, we synthesize recent discoveries on the mechanisms of SCLC plasticity and how these processes may impinge on antitumor immunity.
20 citations
TL;DR: A model in which YTHDC2 binds transcripts independent of m6A status and regulates gene expression during multiple stages of meiosis by distinct mechanisms is proposed.
Abstract: In this study, Saito et al. sought to understand how the N6-methyladenosine (m6A) reader and RNA helicase YTHDC2 switches cells from mitotic to meiotic gene expression programs. Their findings provide insight into YTHDC2's mechanism, and they propose a model in which YTHDC2 binds transcripts independent of m6A status and regulates gene expression during multiple stages of meiosis by distinct mechanisms.
17 citations
TL;DR: These findings provide evidence that Xist imprinting sustains embryonic development and that autosomal noncanonical imprinting restrains placental overgrowth.
Abstract: In this study, Matoba et al. use a combinatorial maternal KO of Xist, a noncanonical imprinted gene whose LOI causes aberrant transient maternal X-chromosome inactivation (XCI) at preimplantation, and show that prevention of the transient maternal XCI greatly restores the development of Eed matKO embryos. Their findings provide evidence that Xist imprinting sustains embryonic development and that autosomal noncanonical imprinting restrains placental overgrowth.
15 citations
TL;DR: These findings expose an intricate link between mRNA homeostasis and mTORC1 activity that must be maintained for normal dynamics of cell state transitions.
Abstract: Here, Huth et al. investigated the role of components of the nonsense-mediated mRNA decay (NMD) pathway in regulating embryonic stem cell (ESC) differentiation, and show that NMD controls expression levels of the translation initiation factor Eif4a2 and its premature termination codon-encoding isoform (Eif4a2PTC). Their findings expose an intricate link between mRNA homeostasis and mTORC1 activity that must be maintained for normal dynamics of cell state transitions.
12 citations
TL;DR: In this review, Bewersdorf and Abdel-Wahab discuss the development of promising new molecular targeted approaches for AML, including menin inhibition, novel IDH1/2 inhibitors, and preclinical means to target TET2, ASXL1, and RNA splicing factor mutations.
Abstract: In this review, Bewersdorf and Abdel-Wahab discuss the development of promising new molecular targeted approaches for AML, including menin inhibition, novel IDH1/2 inhibitors, and preclinical means to target TET2, ASXL1, and RNA splicing factor mutations.
12 citations
TL;DR: Several mammalian BEN domain (BD) factors are characterized, including from two NACC family BTB-BEN proteins and from BEND3, which has four BDs, and structural insights into sequence-specific DNA binding by mammalian BEN proteins are provided.
Abstract: In this study, Zheng et al. investigated how BEN factors, a recently recognized DNA binding module, identify their targets in humans. They characterize several mammalian BEN domain (BD) factors, including from two NACC family BTB-BEN proteins and from BEND3, which has four BDs, and provide structural insights into sequence-specific DNA binding by mammalian BEN proteins.
12 citations
TL;DR: This work shows that DOT1L, the sole H3K79 methyltransferase, is required for spermatogonial stem cell self-renewal and provides an epigenetic paradigm for regulation of sperMatogonialstem cells.
Abstract: Here, Lin et al. investigated the mechanisms underlying self-renewal of spermatogonial stem cells and show that DOT1L, the sole H3K79 methyltransferase, is required for spermatogonial stem cell self-renewal. Their findings identify an essential function for DOT1L in adult stem cells and provide an epigenetic paradigm for regulation of spermatogonial stem cells.
TL;DR: Bonnet et al. as mentioned in this paper investigated how levels of monoubiquitination of histone H2A at lysine 118 (H2Aub1) must be balanced for Polycomb repression.
Abstract: Here, Bonnet et al. investigated how levels of monoubiquitination of histone H2A at lysine 118 (H2Aub1) must be balanced for Polycomb repression, and show that in early embryos H2Aub1 is enriched at Polycomb target genes, where it facilitates H3K27me3 deposition by PRC2 to mark genes for repression. They show that PR-DUB acts as a rheostat that removes excessive H2Aub1 that, although deposited by PRC1, antagonizes PRC1-mediated chromatin compaction.
TL;DR: TriBE-STAMP as mentioned in this paper is an approach for single-molecule detection of the target RNAs of two RNA binding proteins simultaneously in cells, which can be applied to the cytoplasmic m6A reader proteins YTHDF1, 2, and 3.
Abstract: RNA-binding proteins (RBPs) regulate nearly every aspect of mRNA processing and are important regulators of gene expression in cells. However, current methods for transcriptome-wide identification of RBP targets are limited since they examine only a single RBP at a time and since they do not provide information on the individual RNA molecules that are bound by a given RBP. Here, we overcome these limitations by developing TRIBE-STAMP, an approach for single-molecule detection of the target RNAs of two RNA binding proteins simultaneously in cells. We apply TRIBE-STAMP to the cytoplasmic m6A reader proteins YTHDF1, 2, and 3 and discover that individual mRNA molecules can be bound by more than one YTHDF protein throughout their lifetime, providing new insights into the function of YTHDF proteins in cells. TRIBE-STAMP is a highly versatile approach that enables single-molecule analysis of the targets of RBP pairs simultaneously in the same cells.
TL;DR: This study coupled a bioinformatics-based approach with mass spectrometry analyses to demonstrate that CHD4 interacts with the core cardiac transcription factors GATA4, NKX2-5, and TBX5 during embryonic heart development, thus providing new insights into how mutations in theCHD4 protein lead to cardiac-specific disease states.
Abstract: In this study, Robbe et al. investigated how CHD4/NuRD is localized to specific cardiac target genes, as neither CHD4 nor NuRD can directly bind DNA. They coupled a bioinformatics-based approach with mass spectrometry analyses to demonstrate that CHD4 interacts with the core cardiac transcription factors GATA4, NKX2-5, and TBX5 during embryonic heart development, thus providing new insights into how mutations in the CHD4 protein lead to cardiac-specific disease states.
TL;DR: A striking disconnection between transcriptional control and chromatin architecture is found and nearly all Sox2 transcriptional activation is traced to a small number of key transcription factor binding sites, whose deletions have no effect on promoter–enhancer interaction frequencies or topological domain organization.
Abstract: Here, Taylor et al. investigated how distal regulatory elements control gene transcription and chromatin topology in lineage specification during development. Through allele-specific genome editing and chromatin interaction analyses of the Sox2 locus in mouse embryonic stem cells, they found a striking disconnection between transcriptional control and chromatin architecture, and traced nearly all Sox2 transcriptional activation to a small number of key transcription factor binding sites, whose deletions have no effect on promoter–enhancer interaction frequencies or topological domain organization.
TL;DR: It is shown that PPARγ isoforms have specific and separable metabolic functions that may be targeted to improve therapy for insulin resistance and diabetes.
Abstract: In this study, Hu et al. investigated the specific functions of the two main PPARγ isoforms by generating mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. They show that PPARγ isoforms have specific and separable metabolic functions that may be targeted to improve therapy for insulin resistance and diabetes.
TL;DR: Here, Eisemann and Wechsler-Reya review recent preclinical and clinical studies that have identified mechanisms of immune evasion in medulloblastoma, and highlight possible therapeutic interventions that may give new hope to medullOBlastoma patients and their families.
Abstract: Here, Eisemann and Wechsler-Reya review recent preclinical and clinical studies that have identified mechanisms of immune evasion in medulloblastoma, and highlight possible therapeutic interventions that may give new hope to medulloblastoma patients and their families.
TL;DR: It is reported that robust ribosomal RNA (rRNA) synthesis and nucleolar maturation are essential for exit from the 2C state.
Abstract: In this study, Xie et al. investigated the mechanisms and requirement for MERVL and two-cell (2C) gene up-regulation in mammalian embryos, and report that robust ribosomal RNA (rRNA) synthesis and nucleolar maturation are essential for exit from the 2C state. Their findings reveal an intriguing link between rRNA synthesis, nucleolar maturation, and gene repression during early development.
TL;DR: It is shown that point mutations that impair the interactions between D and the C-Eb membrane complex reduce the efficiency of DPA import during sporulation and reciprocally accelerate DPA release during germination.
Abstract: Here, Gao et al. investigated the minimal set of proteins encoded in the Bacillus subtilis spoVA operon required for small molecule dipicolinic acid (DPA) import, which plays a central role in both the stress resistance of the dormant spore and its exit from dormancy during germination, and demonstrate that these proteins form a membrane complex. The authors propose a model in which DPA transport into spores involves cycles of unplugging then replugging the C–Eb membrane channel, while nutrient detection during germination triggers DPA release by unplugging it.
TL;DR: It is demonstrated that the DNA repair factor HMCES strongly suppresses deletions without significantly affecting other parameters of somatic hypermutation in mouse and human B cells, thereby facilitating the production of antigen-specific antibodies.
Abstract: Here, Wu et al. demonstrate that the DNA repair factor HMCES strongly suppresses deletions without significantly affecting other parameters of somatic hypermutation in mouse and human B cells, thereby facilitating the production of antigen-specific antibodies. Their findings lead to a novel model for the protection of Ig gene integrity during SHM in which abasic site cross-linking by HMCES intercedes at a critical juncture during processing of vulnerable gapped DNA intermediates by BER and MMR enzymes.
TL;DR: It is demonstrated that macrophages are mobilized ahead of Schwann cells in the nerve bridge after transection injury to participate in building regeneration tracks, which requires the function of guidance receptor Plexin-B2, which is robustly up-regulated in infiltrating macrophage in injured nerve.
Abstract: In this study, Li et al. investigated the mechanisms underlying the regeneration of peripheral nerves, which is guided by regeneration tracks formed through an interplay of many cell types. They demonstrate that macrophages are mobilized ahead of Schwann cells in the nerve bridge after transection injury to participate in building regeneration tracks. This requires the function of guidance receptor Plexin-B2, which is robustly up-regulated in infiltrating macrophages in injured nerve.
TL;DR: The results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.
Abstract: In this study, Yin et al. show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB component Rela underpins senescence surveillance. Their results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.
TL;DR: In this paper , the authors identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged acute myeloid leukemia.
Abstract: Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. Here, we identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged AML, where MEF2D displays partially redundant functions with its paralog, MEF2C. Rapid transcription factor degradation followed by measurements of genome-wide transcription rates and superresolution microscopy revealed that MEF2D and IRF8 form a distinct core regulatory module with a narrow direct transcriptional program that includes activation of the key oncogenes MYC, HOXA9, and BCL2. Our study illustrates a mechanism of context-specific transcriptional addiction whereby a specific AML subclass depends on a highly specialized core regulatory module to directly enforce expression of common leukemia oncogenes.
TL;DR: It is found that loss of H3K9me3 caused by SETDB1 depletion was associated with increased recruitment of CTCF to >1600 DNA binding motifs contained within SINE B2 repeats, a previously unidentified target ofSETDB1-mediated repression.
Abstract: Here, Gualdrini et al. found that loss of H3K9me3 caused by SETDB1 depletion was associated with increased recruitment of CTCF to >1600 DNA binding motifs contained within SINE B2 repeats, a previously unidentified target of SETDB1-mediated repression. Their findings suggest a role for H3K9me3 in restraining genomic distribution and activity of CTCF, influencing chromatin organization and gene regulation.
TL;DR: A novel mechanistic role of the m96cl is identified in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.
Abstract: Here, Kundu et al. investigated the role of the microRNA-183/96/182 cluster (m96cl) in lung cancer and used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of K-Ras mutant autochthonous lung adenocarcinomas. Overall, the authors identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.
TL;DR: In this article , the authors describe optimized conditions to continuously expand murine alveolar type 2 (AT2) cells, a prominent cell of origin for lung adenocarcinoma, in organoid culture.
Abstract: Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases. While existing genetically engineered mouse models (GEMMs) recapitulate the histological progression and transcriptional evolution of human LUAD, they are time-consuming and technically demanding. In contrast, cell line transplant models are fast and flexible, but these models fail to capture the full spectrum of disease progression. Organoid technologies provide a means to create next-generation cancer models that integrate the most advantageous features of autochthonous and transplant-based systems. However, robust and faithful LUAD organoid platforms are currently lacking. Here, we describe optimized conditions to continuously expand murine alveolar type 2 (AT2) cells, a prominent cell of origin for LUAD, in organoid culture. These organoids display canonical features of AT2 cells, including marker gene expression, the presence of lamellar bodies, and an ability to differentiate into the AT1 lineage. We used this system to develop flexible and versatile immunocompetent organoid-based models of KRAS , BRAF , and ALK mutant LUAD. Notably, organoid-based tumors display extensive burden and complete penetrance and are histopathologically indistinguishable from their autochthonous counterparts. Altogether, this organoid platform is a powerful, versatile new model system to study LUAD.
TL;DR: In this paper , the authors show that DriD binds a specific promoter DNA site via its N-terminal HTH domain to activate transcription of genes, including the cell division inhibitor didA .
Abstract: DNA damage repair systems are critical for genomic integrity. However, they must be coordinated with DNA replication and cell division to ensure accurate genomic transmission. In most bacteria, this coordination is mediated by the SOS response through LexA, which triggers a halt in cell division until repair is completed. Recently, an SOS-independent damage response system was revealed in Caulobacter crescentus. This pathway is controlled by the transcription activator, DriD, but how DriD senses and signals DNA damage is unknown. To address this question, we performed biochemical, cellular, and structural studies. We show that DriD binds a specific promoter DNA site via its N-terminal HTH domain to activate transcription of genes, including the cell division inhibitor didA . A structure of the C-terminal portion of DriD revealed a WYL motif domain linked to a WCX dimerization domain. Strikingly, we found that DriD binds ssDNA between the WYL and WCX domains. Comparison of apo and ssDNA-bound DriD structures reveals that ssDNA binding orders and orients the DriD domains, indicating a mechanism for ssDNA-mediated operator DNA binding activation. Biochemical and in vivo studies support the structural model. Our data thus reveal the molecular mechanism underpinning an SOS-independent DNA damage repair pathway.
TL;DR: In this paper , the authors characterized the fusion protein produced by the EPC1-PHF1 translocation and showed that most chromosomal translocations linked to these sarcomas employ the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes leading to mislocalization of histone marks.
Abstract: Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with Endometrial Stromal Sarcomas (ESS) and Ossifying FibroMyxoid Tumors (OFMT) leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a co-activator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a mega-complex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome, in particular over an entire topologically- associating domain including part of the HOXD cluster. This is linked to aberrant gene expression, most notably increased expression of PRC2 target genes. Furthermore, we show that JAZF1, implicated with a PRC2 component in the most frequent translocation in ESS, JAZF1-SUZ12, is a potent transcription activator that physically associates with NuA4/TIP60, its fusion creating similar outcomes as EPC1-PHF1. Importantly, the specific increased expression of PRC2 targets/HOX genes was also confirmed with ESS patient samples. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas employ the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes leading to mislocalization of histone marks and aberrant polycomb target gene expression.
TL;DR: A genome-wide screening strategy is developed and an RNA binding protein, RBM33, is found that directs the nuclear export of NORAD and numerous other transcripts, revealing a long-sought nuclear export pathway for transcripts with GC-rich sequences.
Abstract: In this study, Thomas et al. developed a genome-wide screening strategy to investigate the mechanism of export of NORAD, an intronless cytoplasmic long noncoding RNA (lncRNA), and found an RNA binding protein, RBM33, that directs the nuclear export of NORAD and numerous other transcripts. These results provide a broadly applicable strategy for the genetic dissection of nuclear export mechanisms and reveal a long-sought nuclear export pathway for transcripts with GC-rich sequences.
TL;DR: It is reported that extracytoplasmic IDRs in Bacillus subtilis are required for cell wall homeostasis, and data support a model in which the RsgI-σI signaling system and PBP1 represent complementary pathways to repair gaps in the PG meshwork.
Abstract: In this study, Brunet et al. investigated the roles of intrinsically disordered protein regions (IDRs) in bacteria, and report that extracytoplasmic IDRs in Bacillus subtilis are required for cell wall homeostasis. Their data support a model in which the IDR on anti-σ factor RsgI senses gaps in the PG meshwork and activates σI, while the IDR on PBP1 directs the synthase to these sites to fortify them.