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Transcription"“replication interactions reveal bacterial genome regulation

Pountain, Andrew W.; Jiang, Peien; Yao, Tianyou; Homaee, Ehsan; Guan, Yichao; McDonald, Kevin J.C.; Podkowik, Magdalena; Shopsin, Bo; Torres, Victor J.; Golding, Ido; Yanai, Itai
Organisms determine the transcription rates of thousands of genes through a few modes of regulation that recur across the genome1. In bacteria, the relationship between the regulatory architecture of a gene and its expression is well understood for individual model gene circuits2,3. However, a broader perspective of these dynamics at the genome scale is lacking, in part because bacterial transcriptomics has hitherto captured only a static snapshot of expression averaged across millions of cells4. As a result, the full diversity of gene expression dynamics and their relation to regulatory architecture remains unknown. Here we present a novel genome-wide classification of regulatory modes based on the transcriptional response of each gene to its own replication, which we term the transcription"“replication interaction profile (TRIP). Analysing single-bacterium RNA-sequencing data, we found that the response to the universal perturbation of chromosomal replication integrates biological regulatory factors with biophysical molecular events on the chromosome to reveal the local regulatory context of a gene. Whereas the TRIPs of many genes conform to a gene dosage-dependent pattern, others diverge in distinct ways, and this is shaped by factors such as intra-operon position and repression state. By revealing the underlying mechanistic drivers of gene expression heterogeneity, this work provides a quantitative, biophysical framework for modelling replication-dependent expression dynamics.
ISSN: 0028-0836
CID: 5629352

SETD2 mutations do not contribute to clonal fitness in response to chemotherapy in childhood B cell acute lymphoblastic leukemia

Contreras Yametti, Gloria P; Robbins, Gabriel; Chowdhury, Ashfiyah; Narang, Sonali; Ostrow, Talia H; Kilberg, Harrison; Greenberg, Joshua; Kramer, Lindsay; Raetz, Elizabeth; Tsirigos, Aristotelis; Evensen, Nikki A; Carroll, William L
Mutations in genes encoding epigenetic regulators are commonly observed at relapse in B cell acute lymphoblastic leukemia (B-ALL). Loss-of-function mutations in SETD2, an H3K36 methyltransferase, have been observed in B-ALL and other cancers. Previous studies on mutated SETD2 in solid tumors and acute myelogenous leukemia support a role in promoting resistance to DNA damaging agents. We did not observe chemoresistance, an impaired DNA damage response, nor increased mutation frequency in response to thiopurines using CRISPR-mediated knockout in wild-type B-ALL cell lines. Likewise, restoration of SETD2 in cell lines with hemizygous mutations did not increase sensitivity. SETD2 mutations affected the chromatin landscape and transcriptional output that was unique to each cell line. Collectively our data does not support a role for SETD2 mutations in driving clonal evolution and relapse in B-ALL, which is consistent with the lack of enrichment of SETD2 mutations at relapse in most studies.
PMID: 37874744
ISSN: 1029-2403
CID: 5635112

3D Enhancer-promoter networks provide predictive features for gene expression and coregulation in early embryonic lineages

Murphy, Dylan; Salataj, Eralda; Di Giammartino, Dafne Campigli; Rodriguez-Hernaez, Javier; Kloetgen, Andreas; Garg, Vidur; Char, Erin; Uyehara, Christopher M; Ee, Ly-Sha; Lee, UkJin; Stadtfeld, Matthias; Hadjantonakis, Anna-Katerina; Tsirigos, Aristotelis; Polyzos, Alexander; Apostolou, Effie
Mammalian embryogenesis commences with two pivotal and binary cell fate decisions that give rise to three essential lineages: the trophectoderm, the epiblast and the primitive endoderm. Although key signaling pathways and transcription factors that control these early embryonic decisions have been identified, the non-coding regulatory elements through which transcriptional regulators enact these fates remain understudied. Here, we characterize, at a genome-wide scale, enhancer activity and 3D connectivity in embryo-derived stem cell lines that represent each of the early developmental fates. We observe extensive enhancer remodeling and fine-scale 3D chromatin rewiring among the three lineages, which strongly associate with transcriptional changes, although distinct groups of genes are irresponsive to topological changes. In each lineage, a high degree of connectivity, or 'hubness', positively correlates with levels of gene expression and enriches for cell-type specific and essential genes. Genes within 3D hubs also show a significantly stronger probability of coregulation across lineages compared to genes in linear proximity or within the same contact domains. By incorporating 3D chromatin features, we build a predictive model for transcriptional regulation (3D-HiChAT) that outperforms models using only 1D promoter or proximal variables to predict levels and cell-type specificity of gene expression. Using 3D-HiChAT, we identify, in silico, candidate functional enhancers and hubs in each cell lineage, and with CRISPRi experiments, we validate several enhancers that control gene expression in their respective lineages. Our study identifies 3D regulatory hubs associated with the earliest mammalian lineages and describes their relationship to gene expression and cell identity, providing a framework to comprehensively understand lineage-specific transcriptional behaviors.
PMID: 38053013
ISSN: 1545-9985
CID: 5595532

Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy

Mukhopadhyay, Suman; Huang, Hsin-Yi; Lin, Ziyan; Ranieri, Michela; Li, Shuai; Sahu, Soumyadip; Liu, Yingzhuo; Ban, Yi; Guidry, Kayla; Hu, Hai; Lopez, Alfonso; Sherman, Fiona; Tan, Yi Jer; Lee, Yeuan Ting; Armstrong, Amanda P; Dolgalev, Igor; Sahu, Priyanka; Zhang, Tinghu; Lu, Wenchao; Gray, Nathanael S; Christensen, James G; Tang, Tracy T; Velcheti, Vamsidhar; Khodadadi-Jamayran, Alireza; Wong, Kwok-Kin; Neel, Benjamin G
UNLABELLED:Non-small lung cancers (NSCLC) frequently (∼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRASG12C inhibitors (G12Ci) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine-threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components. Several SL genes were confirmed by siRNA/shRNA experiments, and the YAP/TAZ/TEAD pathway was extensively validated in vitro and in mice. Mechanistic studies showed that G12Ci treatment induced gene expression of RHO paralogs and activators, increased RHOA activation, and evoked ROCK-dependent nuclear translocation of YAP. Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic. SIGNIFICANCE/UNASSIGNED:Identification of synthetic lethal genes with KRASG12C using genome-wide CRISPR/Cas9 screening and credentialing of the ability of TEAD inhibition to enhance KRASG12C efficacy provides a roadmap for combination strategies. See related commentary by Johnson and Haigis, p. 4005.
PMID: 37729426
ISSN: 1538-7445
CID: 5606372

KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance

Zavitsanou, Anastasia-Maria; Pillai, Ray; Hao, Yuan; Wu, Warren L; Bartnicki, Eric; Karakousi, Triantafyllia; Rajalingam, Sahith; Herrera, Alberto; Karatza, Angeliki; Rashidfarrokhi, Ali; Solis, Sabrina; Ciampricotti, Metamia; Yeaton, Anna H; Ivanova, Ellie; Wohlhieter, Corrin A; Buus, Terkild B; Hayashi, Makiko; Karadal-Ferrena, Burcu; Pass, Harvey I; Poirier, John T; Rudin, Charles M; Wong, Kwok-Kin; Moreira, Andre L; Khanna, Kamal M; Tsirigos, Aristotelis; Papagiannakopoulos, Thales; Koralov, Sergei B
Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.
PMID: 37889752
ISSN: 2211-1247
CID: 5590262

The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability

Ravn-Boess, Niklas; Roy, Nainita; Hattori, Takamitsu; Bready, Devin; Donaldson, Hayley; Lawson, Christopher; Lapierre, Cathryn; Korman, Aryeh; Rodrick, Tori; Liu, Enze; Frenster, Joshua D; Stephan, Gabriele; Wilcox, Jordan; Corrado, Alexis D; Cai, Julia; Ronnen, Rebecca; Wang, Shuai; Haddock, Sara; Sabio Ortiz, Jonathan; Mishkit, Orin; Khodadadi-Jamayran, Alireza; Tsirigos, Aris; Fenyö, David; Zagzag, David; Drube, Julia; Hoffmann, Carsten; Perna, Fabiana; Jones, Drew R; Possemato, Richard; Koide, Akiko; Koide, Shohei; Park, Christopher Y; Placantonakis, Dimitris G
Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Adhesion G protein-coupled receptors (aGPCRs) have attracted interest for their potential as treatment targets. Here, we show that CD97 (ADGRE5) is the most promising aGPCR target in GBM, by virtue of its de novo expression compared to healthy brain tissue. CD97 knockdown or knockout significantly reduces the tumor initiation capacity of patient-derived GBM cultures (PDGCs) in vitro and in vivo. We find that CD97 promotes glycolytic metabolism via the mitogen-activated protein kinase (MAPK) pathway, which depends on phosphorylation of its C terminus and recruitment of β-arrestin. We also demonstrate that THY1/CD90 is a likely CD97 ligand in GBM. Lastly, we show that an anti-CD97 antibody-drug conjugate selectively kills tumor cells in vitro. Our studies identify CD97 as a regulator of tumor metabolism, elucidate mechanisms of receptor activation and signaling, and provide strong scientific rationale for developing biologics to target it therapeutically in GBM.
PMID: 37938973
ISSN: 2211-1247
CID: 5590372

An Anterior Second Heart Field Enhancer Regulates the Gene Regulatory Network of the Cardiac Outflow Tract

Yamaguchi, Naoko; Chang, Ernest W; Lin, Ziyan; Shekhar, Akshay; Bu, Lei; Khodadadi-Jamayran, Alireza; Tsirigos, Aristotelis; Cen, Yiyun; Phoon, Colin K L; Moskowitz, Ivan P; Park, David S
BACKGROUND/UNASSIGNED:Conotruncal defects due to developmental abnormalities of the outflow tract (OFT) are an important cause of cyanotic congenital heart disease. Dysregulation of transcriptional programs tuned by NKX2-5 (NK2 homeobox 5), GATA6 (GATA binding protein 6), and TBX1 (T-box transcription factor 1) have been implicated in abnormal OFT morphogenesis. However, there remains no consensus on how these transcriptional programs function in a unified gene regulatory network within the OFT. METHODS/UNASSIGNED: RESULTS/UNASSIGNED: CONCLUSIONS/UNASSIGNED:Our results using human and mouse models reveal an essential gene regulatory network of the OFT that requires an anterior second heart field enhancer to link GATA6 with NKX2-5-dependent rotation and septation gene programs.
PMID: 37772400
ISSN: 1524-4539
CID: 5606412

Thinking about scienceI've Been Thinking Daniel C. Dennett Norton, 2023. 464 pp

Yanai, Itai; Lercher, Martin J
A philosopher reflects on his influential interrogations of free will, consciousness, and artificial intelligence.
PMID: 37943930
ISSN: 1095-9203
CID: 5609892

Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma

Dolgalev, Igor; Zhou, Hua; Murrell, Nina; Le, Hortense; Sakellaropoulos, Theodore; Coudray, Nicolas; Zhu, Kelsey; Vasudevaraja, Varshini; Yeaton, Anna; Goparaju, Chandra; Li, Yonghua; Sulaiman, Imran; Tsay, Jun-Chieh J; Meyn, Peter; Mohamed, Hussein; Sydney, Iris; Shiomi, Tomoe; Ramaswami, Sitharam; Narula, Navneet; Kulicke, Ruth; Davis, Fred P; Stransky, Nicolas; Smolen, Gromoslaw A; Cheng, Wei-Yi; Cai, James; Punekar, Salman; Velcheti, Vamsidhar; Sterman, Daniel H; Poirier, J T; Neel, Ben; Wong, Kwok-Kin; Chiriboga, Luis; Heguy, Adriana; Papagiannakopoulos, Thales; Nadorp, Bettina; Snuderl, Matija; Segal, Leopoldo N; Moreira, Andre L; Pass, Harvey I; Tsirigos, Aristotelis
Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.
PMID: 37938580
ISSN: 2041-1723
CID: 5609852

The transcription factor EBF1 non-cell-autonomously regulates cardiac growth and differentiation

Kim, Eugene E; Shekhar, Akshay; Ramachandran, Jayalakshmi; Khodadadi-Jamayran, Alireza; Liu, Fang-Yu; Zhang, Jie; Fishman, Glenn I
Reciprocal interactions between non-myocytes and cardiomyocytes regulate cardiac growth and differentiation. Here, we report that the transcription factor Ebf1 is highly expressed in non-myocytes and potently regulates heart development. Ebf1-deficient hearts display myocardial hypercellularity and reduced cardiomyocyte size, ventricular conduction system hypoplasia, and conduction system disease. Growth abnormalities in Ebf1 knockout hearts are observed as early as embryonic day 13.5. Transcriptional profiling of Ebf1-deficient embryonic cardiac non-myocytes demonstrates dysregulation of Polycomb repressive complex 2 targets, and ATAC-Seq reveals altered chromatin accessibility near many of these same genes. Gene set enrichment analysis of differentially expressed genes in cardiomyocytes isolated from E13.5 hearts of wild-type and mutant mice reveals significant enrichment of MYC targets and, consistent with this finding, we observe increased abundance of MYC in mutant hearts. EBF1-deficient non-myocytes, but not wild-type non-myocytes, are sufficient to induce excessive accumulation of MYC in co-cultured wild-type cardiomyocytes. Finally, we demonstrate that BMP signaling induces Ebf1 expression in embryonic heart cultures and controls a gene program enriched in EBF1 targets. These data reveal a previously unreported non-cell-autonomous pathway controlling cardiac growth and differentiation.
PMID: 37787076
ISSN: 1477-9129
CID: 5606432