Unique role for lncRNA HOTAIR in defining depot-specific gene expression patterns in human adipose-derived stem cells [Research Papers]
Accumulation of fat above the waist is an important risk factor in developing obesity-related comorbidities independently of BMI or total fat mass. Deciphering the gene regulatory programs of the adipose tissue precursor cells within upper body or abdominal (ABD) and lower body or gluteofemoral (GF) depots is important to understand their differential capacity for lipid accumulation, maturation, and disease risk. Previous studies identified the HOX transcript antisense intergenic RNA (HOTAIR) as a GF-specific lncRNA; however, its role in adipose tissue biology is still unclear. Using three different approaches (silencing o...
Source: Genes and Development - June 9, 2022 Category: Genetics & Stem Cells Authors: Erdos, E., Divoux, A., Sandor, K., Halasz, L., Smith, S. R., Osborne, T. F. Tags: Research Papers Source Type: research
RBM33 directs the nuclear export of transcripts containing GC-rich elements [Research Papers]
Although splicing is a major driver of RNA nuclear export, many intronless RNAs are efficiently exported to the cytoplasm through poorly characterized mechanisms. For example, GC-rich sequences promote nuclear export in a splicing-independent manner, but how GC content is recognized and coupled to nuclear export is unknown. Here, we developed a genome-wide screening strategy to investigate the mechanism of export of NORAD, an intronless cytoplasmic long noncoding RNA (lncRNA). This screen revealed an RNA binding protein, RBM33, that directs the nuclear export of NORAD and numerous other transcripts. RBM33 directly binds su...
Source: Genes and Development - June 9, 2022 Category: Genetics & Stem Cells Authors: Thomas, A., Rehfeld, F., Zhang, H., Chang, T.-C., Goodarzi, M., Gillet, F., Mendell, J. T. Tags: Research Papers Source Type: research
Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance [Research Papers]
Senescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-B activity and that SASP-induced endothelial expression of the canonical NF-B component Rela underpins senescence surveillance. Using human liver sinusoidal endothelial ce...
Source: Genes and Development - June 9, 2022 Category: Genetics & Stem Cells Authors: Yin, K., Patten, D., Gough, S., de Barros Goncalves, S., Chan, A., Olan, I., Cassidy, L., Poblocka, M., Zhu, H., Lun, A., Schuijs, M., Young, A., Martinez-Jimenez, C., Halim, T. Y. F., Shetty, S., Narita, M., Hoare, M. Tags: Research Papers Source Type: research
Coming in from the cold: overcoming the hostile immune microenvironment of medulloblastoma [Reviews]
Medulloblastoma is an aggressive brain tumor that occurs predominantly in children. Despite intensive therapy, many patients die of the disease, and novel therapies are desperately needed. Although immunotherapy has shown promise in many cancers, the low mutational burden, limited infiltration of immune effector cells, and immune-suppressive microenvironment of medulloblastoma have led to the assumption that it is unlikely to respond to immunotherapy. However, emerging evidence is challenging this view. Here we review recent preclinical and clinical studies that have identified mechanisms of immune evasion in medulloblasto...
Source: Genes and Development - June 9, 2022 Category: Genetics & Stem Cells Authors: Eisemann, T., Wechsler-Reya, R. J. Tags: Cancer and Disease Models, Immunology Reviews Source Type: research
Endothelial cells give a boost to senescence surveillance [Outlook]
Senescence is a specialized form of cell cycle arrest induced in response to damage and stress. In certain settings, senescent cells can promote their own removal by recruitment of the immune system, a process that is thought to decline in efficiency with age. In this issue of Genes & Development, Yin et al. (pp. 533–549) discover a surprising cross-talk where senescent cells instruct endothelial cells to help organize the clearance of the senescent population. This uncovers yet another layer of complexity in senescent cell biology, with implications for cancer treatment and aging. (Source: Genes and Development)
Source: Genes and Development - June 9, 2022 Category: Genetics & Stem Cells Authors: Sampaio Goncalves, D., Keyes, W. M. Tags: Cancer and Disease Models Outlook Source Type: research
Functional dissection of human mitotic genes using CRISPR-Cas9 tiling screens [Resource/Methodology]
The identity of human protein-coding genes is well known, yet our in-depth knowledge of their molecular functions and domain architecture remains limited by shortcomings in homology-based predictions and experimental approaches focused on whole-gene depletion. To bridge this knowledge gap, we developed a method that leverages CRISPR–Cas9-induced mutations across protein-coding genes for the a priori identification of functional regions at the sequence level. As a test case, we applied this method to 48 human mitotic genes, revealing hundreds of regions required for cell proliferation, including domains that were expe...
Source: Genes and Development - April 29, 2022 Category: Genetics & Stem Cells Authors: Herman, J. A., Arora, S., Carter, L., Zhu, J., Biggins, S., Paddison, P. J. Tags: Resource/Methodology Source Type: research
Noncanonical imprinting sustains embryonic development and restrains placental overgrowth [Research Papers]
Genomic imprinting regulates parental origin-dependent monoallelic gene expression. It is mediated by either germline differential methylation of DNA (canonical imprinting) or oocyte-derived H3K27me3 (noncanonical imprinting) in mice. Depletion of Eed, an essential component of Polycomb repressive complex 2, results in genome-wide loss of H3K27me3 in oocytes, which causes loss of noncanonical imprinting (LOI) in embryos. Although Eed maternal KO (matKO) embryos show partial lethality after implantation, it is unknown whether LOI itself contributes to the developmental phenotypes of these embryos, which makes it unclear whe...
Source: Genes and Development - April 29, 2022 Category: Genetics & Stem Cells Authors: Matoba, S., Kozuka, C., Miura, K., Inoue, K., Kumon, M., Hayashi, R., Ohhata, T., Ogura, A., Inoue, A. Tags: Research Papers Source Type: research
CHD4 is recruited by GATA4 and NKX2-5 to repress noncardiac gene programs in the developing heart [Research Papers]
The nucleosome remodeling and deacetylase (NuRD) complex is one of the central chromatin remodeling complexes that mediates gene repression. NuRD is essential for numerous developmental events, including heart development. Clinical and genetic studies have provided direct evidence for the role of chromodomain helicase DNA-binding protein 4 (CHD4), the catalytic component of NuRD, in congenital heart disease (CHD), including atrial and ventricular septal defects. Furthermore, it has been demonstrated that CHD4 is essential for mammalian cardiomyocyte formation and function. A key unresolved question is how CHD4/NuRD is loca...
Source: Genes and Development - April 29, 2022 Category: Genetics & Stem Cells Authors: Robbe, Z. L., Shi, W., Wasson, L. K., Scialdone, A. P., Wilczewski, C. M., Sheng, X., Hepperla, A. J., Akerberg, B. N., Pu, W. T., Cristea, I. M., Davis, I. J., Conlon, F. L. Tags: Research Papers Source Type: research
In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation [Research Papers]
Genome organization plays a pivotal role in transcription, but how transcription factors (TFs) rewire the structure of the genome to initiate and maintain the programs that lead to oncogenic transformation remains poorly understood. Acute promyelocytic leukemia (APL) is a fatal subtype of leukemia driven by a chromosomal translocation between the promyelocytic leukemia (PML) and retinoic acid receptor α (RARα) genes. We used primary hematopoietic stem and progenitor cells (HSPCs) and leukemic blasts that express the fusion protein PML-RARα as a paradigm to temporally dissect the dynamic changes in the epi...
Source: Genes and Development - April 29, 2022 Category: Genetics & Stem Cells Authors: Mas, G., Santoro, F., Blanco, E., Gamarra Figueroa, G. P., Le Dily, F., Frige, G., Vidal, E., Mugianesi, F., Ballare, C., Gutierrez, A., Sparavier, A., Marti-Renom, M. A., Minucci, S., Di Croce, L. Tags: Research Papers Source Type: research
HMCES protects immunoglobulin genes specifically from deletions during somatic hypermutation [Research Papers]
Somatic hypermutation (SHM) produces point mutations in immunoglobulin (Ig) genes in B cells when uracils created by the activation-induced deaminase are processed in a mutagenic manner by enzymes of the base excision repair (BER) and mismatch repair (MMR) pathways. Such uracil processing creates DNA strand breaks and is susceptible to the generation of deleterious deletions. Here, we demonstrate that the DNA repair factor HMCES strongly suppresses deletions without significantly affecting other parameters of SHM in mouse and human B cells, thereby facilitating the production of antigen-specific antibodies. The deletion-pr...
Source: Genes and Development - April 29, 2022 Category: Genetics & Stem Cells Authors: Wu, L., Shukla, V., Yadavalli, A. D., Dinesh, R. K., Xu, D., Rao, A., Schatz, D. G. Tags: Research Papers Source Type: research
H3K9 trimethylation in active chromatin restricts the usage of functional CTCF sites in SINE B2 repeats [Research Papers]
Six methyltransferases divide labor in establishing genomic profiles of histone H3 lysine 9 methylation (H3K9me), an epigenomic modification controlling constitutive heterochromatin, gene repression, and silencing of retroelements. Among them, SETDB1 is recruited to active chromatin domains to silence the expression of endogenous retroviruses. In the context of experiments aimed at determining the impact of SETDB1 on stimulus-inducible gene expression in macrophages, we found that loss of H3K9me3 caused by SETDB1 depletion was associated with increased recruitment of CTCF to >1600 DNA binding motifs contained within SIN...
Source: Genes and Development - April 29, 2022 Category: Genetics & Stem Cells Authors: Gualdrini, F., Polletti, S., Simonatto, M., Prosperini, E., Pileri, F., Natoli, G. Tags: Research Papers Source Type: research
Topography of histone H3-H4 interaction with the Hat1-Hat2 acetyltransferase complex [Research Communications]
Chaperones influence histone conformation and intermolecular interaction in multiprotein complexes, and the structures obtained with full-length histones often provide more accurate and comprehensive views. Here, our structure of the Hat1–Hat2 acetyltransferase complex bound to Asf1–H3–H4 shows that the core domains of H3 and H4 are involved in binding Hat1 and Hat2, and the N-terminal tail of H3 makes extensive interaction with Hat2. These findings expand the knowledge about histone–protein interaction and implicate a function of Hat2/RbAp46/48, which is a versatile histone chaperone found in many ...
Source: Genes and Development - April 29, 2022 Category: Genetics & Stem Cells Authors: Yue, Y., Yang, W.-S., Zhang, L., Liu, C.-P., Xu, R.-M. Tags: Research Communications Source Type: research
Roles of vimentin in health and disease [Reviews]
More than 27 yr ago, the vimentin knockout (Vim–/–) mouse was reported to develop and reproduce without an obvious phenotype, implying that this major cytoskeletal protein was nonessential. Subsequently, comprehensive and careful analyses have revealed numerous phenotypes in Vim–/– mice and their organs, tissues, and cells, frequently reflecting altered responses in the recovery of tissues following various insults or injuries. These findings have been supported by cell-based experiments demonstrating that vimentin intermediate filaments (IFs) play a critical role in regulating cell mechanics and ar...
Source: Genes and Development - April 29, 2022 Category: Genetics & Stem Cells Authors: Ridge, K. M., Eriksson, J. E., Pekny, M., Goldman, R. D. Tags: Cancer and Disease Models Reviews Source Type: research
A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia [Research Papers]
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 transcrip...
Source: Genes and Development - March 22, 2022 Category: Genetics & Stem Cells Authors: Harada, T., Heshmati, Y., Kalfon, J., Perez, M. W., Xavier Ferrucio, J., Ewers, J., Hubbell Engler, B., Kossenkov, A., Ellegast, J. M., Yi, J. S., Bowker, A., Zhu, Q., Eagle, K., Liu, T., Kai, Y., Dempster, J. M., Kugener, G., Wickramasinghe, J., Herbert, Tags: Research Papers Source Type: research
NMD is required for timely cell fate transitions by fine-tuning gene expression and regulating translation [Research Papers]
Cell fate transitions depend on balanced rewiring of transcription and translation programs to mediate ordered developmental progression. Components of the nonsense-mediated mRNA decay (NMD) pathway have been implicated in regulating embryonic stem cell (ESC) differentiation, but the exact mechanism is unclear. Here we show that NMD controls expression levels of the translation initiation factor Eif4a2 and its premature termination codon-encoding isoform (Eif4a2PTC). NMD deficiency leads to translation of the truncated eIF4A2PTC protein. eIF4A2PTC elicits increased mTORC1 activity and translation rates and causes different...
Source: Genes and Development - March 22, 2022 Category: Genetics & Stem Cells Authors: Huth, M., Santini, L., Galimberti, E., Ramesmayer, J., Titz-Teixeira, F., Sehlke, R., Oberhuemer, M., Stummer, S., Herzog, V., Garmhausen, M., Romeike, M., Chugunova, A., Leesch, F., Holcik, L., Weipoltshammer, K., Lackner, A., Schoefer, C., von Haeseler, Tags: Research Papers Source Type: research
