REST is a major negative regulator of endocrine differentiation during pancreas organogenesis [Research Papers]
Multiple transcription factors have been shown to promote pancreatic β-cell differentiation, yet much less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic Rest knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation. REST inhibition also ...
Source: Genes and Development - September 1, 2021 Category: Genetics & Stem Cells Authors: Rovira, M., Atla, G., Maestro, M. A., Grau, V., Garcia-Hurtado, J., Maqueda, M., Mosquera, J. L., Yamada, Y., Kerr-Conte, J., Pattou, F., Ferrer, J. Tags: Research Papers Source Type: research
Dissecting dual roles of MyoD during lineage conversion to mature myocytes and myogenic stem cells [Research Papers]
The generation of myotubes from fibroblasts upon forced MyoD expression is a classic example of transcription factor-induced reprogramming. We recently discovered that additional modulation of signaling pathways with small molecules facilitates reprogramming to more primitive induced myogenic progenitor cells (iMPCs). Here, we dissected the transcriptional and epigenetic dynamics of mouse fibroblasts undergoing reprogramming to either myotubes or iMPCs using a MyoD-inducible transgenic model. Induction of MyoD in fibroblasts combined with small molecules generated Pax7+ iMPCs with high similarity to primary muscle stem cel...
Source: Genes and Development - September 1, 2021 Category: Genetics & Stem Cells Authors: Yagi, M., Ji, F., Charlton, J., Cristea, S., Messemer, K., Horwitz, N., Di Stefano, B., Tsopoulidis, N., Hoetker, M. S., Huebner, A. J., Bar-Nur, O., Almada, A. E., Yamamoto, M., Patelunas, A., Goldhamer, D. J., Wagers, A. J., Michor, F., Meissner, A., Sa Tags: Research Papers Source Type: research
Single-cell atlas reveals meningeal leukocyte heterogeneity in the developing mouse brain [Resource/Methodology]
The meninges are important for brain development and pathology. Using single-cell RNA sequencing, we have generated the first comprehensive transcriptional atlas of neonatal mouse meningeal leukocytes under normal conditions and after perinatal brain injury. We identified almost all known leukocyte subtypes and found differences between neonatal and adult border-associated macrophages, thus highlighting that neonatal border-associated macrophages are functionally immature with regards to immune responses compared with their adult counterparts. We also identified novel meningeal microglia-like cell populations that may part...
Source: Genes and Development - August 2, 2021 Category: Genetics & Stem Cells Authors: Zelco, A., Börjesson, V., de Kanter, J. K., Lebrero-Fernandez, C., Lauschke, V. M., Rocha-Ferreira, E., Nilsson, G., Nair, S., Svedin, P., Bemark, M., Hagberg, H., Mallard, C., Holstege, F. C. P., Wang, X. Tags: Resource/Methodology Source Type: research
The Pol II preinitiation complex (PIC) influences Mediator binding but not promoter-enhancer looping [Research Papers]
Knowledge of how Mediator and TFIID cross-talk contributes to promoter–enhancer (P-E) communication is important for elucidating the mechanism of enhancer function. We conducted an shRNA knockdown screen in murine embryonic stem cells to identify the functional overlap between Mediator and TFIID subunits on gene expression. Auxin-inducible degrons were constructed for TAF12 and MED4, the subunits eliciting the greatest overlap. Degradation of TAF12 led to a dramatic genome-wide decrease in gene expression accompanied by destruction of TFIID, loss of Pol II preinitiation complex (PIC) at promoters, and significantly d...
Source: Genes and Development - August 2, 2021 Category: Genetics & Stem Cells Authors: Sun, F., Sun, T., Kronenberg, M., Tan, X., Huang, C., Carey, M. F. Tags: Research Papers Source Type: research
Protein phosphatase 4 controls circadian clock dynamics by modulating CLOCK/BMAL1 activity [Research Papers]
In all organisms with circadian clocks, post-translational modifications of clock proteins control the dynamics of circadian rhythms, with phosphorylation playing a dominant role. All major clock proteins are highly phosphorylated, and many kinases have been described to be responsible. In contrast, it is largely unclear whether and to what extent their counterparts, the phosphatases, play an equally crucial role. To investigate this, we performed a systematic RNAi screen in human cells and identified protein phosphatase 4 (PPP4) with its regulatory subunit PPP4R2 as critical components of the circadian system in both mamm...
Source: Genes and Development - August 2, 2021 Category: Genetics & Stem Cells Authors: Klemz, S., Wallach, T., Korge, S., Rosing, M., Klemz, R., Maier, B., Fiorenza, N. C., Kaymak, I., Fritzsche, A. K., Herzog, E. D., Stanewsky, R., Kramer, A. Tags: Research Papers Source Type: research
ZFP451-mediated SUMOylation of SATB2 drives embryonic stem cell differentiation [Research Papers]
The establishment of cell fates involves alterations of transcription factor repertoires and repurposing of transcription factors by post-translational modifications. In embryonic stem cells (ESCs), the chromatin organizers SATB2 and SATB1 balance pluripotency and differentiation by activating and repressing pluripotency genes, respectively. Here, we show that conditional Satb2 gene inactivation weakens ESC pluripotency, and we identify SUMO2 modification of SATB2 by the E3 ligase ZFP451 as a potential driver of ESC differentiation. Mutations of two SUMO-acceptor lysines of Satb2 (Satb2K ->R) or knockout of Zfp451 impai...
Source: Genes and Development - August 2, 2021 Category: Genetics & Stem Cells Authors: Antonio Urrutia, G., Ramachandran, H., Cauchy, P., Boo, K., Ramamoorthy, S., Boller, S., Dogan, E., Clapes, T., Trompouki, E., Torres-Padilla, M.-E., Palvimo, J. J., Pichler, A., Grosschedl, R. Tags: Research Papers Source Type: research
Nopp140-chaperoned 2'-O-methylation of small nuclear RNAs in Cajal bodies ensures splicing fidelity [Research Papers]
Spliceosomal small nuclear RNAs (snRNAs) are modified by small Cajal body (CB)-specific ribonucleoproteins (scaRNPs) to ensure snRNP biogenesis and pre-mRNA splicing. However, the function and subcellular site of snRNA modification are largely unknown. We show that CB localization of the protein Nopp140 is essential for concentration of scaRNPs in that nuclear condensate; and that phosphorylation by casein kinase 2 (CK2) at ~80 serines targets Nopp140 to CBs. Transiting through CBs, snRNAs are apparently modified by scaRNPs. Indeed, Nopp140 knockdown-mediated release of scaRNPs from CBs severely compromises 2'-O-methylatio...
Source: Genes and Development - August 2, 2021 Category: Genetics & Stem Cells Authors: Bizarro, J., Deryusheva, S., Wacheul, L., Gupta, V., Ernst, F. G. M., Lafontaine, D. L. J., Gall, J. G., Meier, U. T. Tags: Research Papers Source Type: research
miR-200 deficiency promotes lung cancer metastasis by activating Notch signaling in cancer-associated fibroblasts [Research Papers]
Lung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying cellular and molecular mechanisms remain largely elusive. Here, we identified miR-200 miRNAs as potent suppressors for lung adenocarcinoma metastasis. miR-200 expression is specifically repressed in mouse metastatic lung adenocarcinomas, and miR-200 decrease strongly correlates with poor patient survival. Consistently, deletion of mir-200c/141 in the KrasLSL-G12D/+; Trp53flox/flox lung adenocarcinoma mouse model significantly promo...
Source: Genes and Development - August 2, 2021 Category: Genetics & Stem Cells Authors: Xue, B., Chuang, C.-H., Prosser, H. M., Fuziwara, C. S., Chan, C., Sahasrabudhe, N., Kühn, M., Wu, Y., Chen, J., Biton, A., Chen, C., Wilkinson, J. E., McManus, M. T., Bradley, A., Winslow, M. M., Su, B., He, L. Tags: Research Papers Source Type: research
Transient genomic instability drives tumorigenesis through accelerated clonal evolution [Research Papers]
Abnormal numerical and structural chromosome content is frequently found in human cancer. To test the role of aneuploidy in tumor initiation and progression, we generated mice with random aneuploidies by transient induction of polo-like kinase 4 (Plk4), a master regulator of centrosome number. Short-term chromosome instability (CIN) from transient Plk4 induction resulted in formation of aggressive T-cell lymphomas in mice with heterozygous inactivation of one p53 allele and accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphoma-initiating cells with a specific karyotype profi...
Source: Genes and Development - August 2, 2021 Category: Genetics & Stem Cells Authors: Shoshani, O., Bakker, B., de Haan, L., Tijhuis, A. E., Wang, Y., Kim, D. H., Maldonado, M., Demarest, M. A., Artates, J., Zhengyu, O., Mark, A., Wardenaar, R., Sasik, R., Spierings, D. C. J., Vitre, B., Fisch, K., Foijer, F., Cleveland, D. W. Tags: Research Papers Source Type: research
Clonal selection of stable aneuploidies in progenitor cells drives high-prevalence tumorigenesis [Research Papers]
Chromosome gains and losses are a frequent feature of human cancers. However, how these aberrations can outweigh the detrimental effects of aneuploidy remains unclear. An initial comparison of existing chromosomal instability (CIN) mouse models suggests that aneuploidy accumulates to low levels in these animals. We therefore developed a novel mouse model that enables unprecedented levels of chromosome missegregation in the adult animal. At the earliest stages of T-cell development, cells with random chromosome gains and/or losses are selected against, but CIN eventually results in the expansion of progenitors with clonal c...
Source: Genes and Development - August 2, 2021 Category: Genetics & Stem Cells Authors: Trakala, M., Aggarwal, M., Sniffen, C., Zasadil, L., Carroll, A., Ma, D., Su, X. A., Wangsa, D., Meyer, A., Sieben, C. J., Zhong, J., Hsu, P.-h., Paradis, G., Ried, T., Holland, A., Van Deursen, J., Amon, A. Tags: Research Papers Source Type: research
BMAL1 dephosphorylation determines the pace of the circadian clock [Outlook]
In mammals, virtually all body cells harbor cell-autonomous and self-sustained circadian oscillators that rely on delayed negative feedback loops in gene expression. Transcriptional activation and repression play a major role in keeping these clocks ticking, but numerous post-translational mechanisms—and particularly the phosphorylation of core clock components by protein kinases—are also critically involved in setting the pace of these timekeepers. In this issue of Genes & Development, Klemz and colleagues (pp. 1161–1174) now show how dephosphorylation of BMAL1 by protein phosphatase 4 (PPP4) partici...
Source: Genes and Development - August 2, 2021 Category: Genetics & Stem Cells Authors: Schibler, U. Tags: Chromatin and Gene Expression Outlook Source Type: research
Solving the chromosome puzzle of aneuploidy in cancer [Outlook]
Chromosome instability (CIN) and aneuploidy are hallmarks of cancer cells, typically associated with aggressiveness and poor outcomes. Historically, the causative link between aneuploidy and cancer has been difficult to study due to its intrinsic complexity and the poor fitness of aneuploid cells. In this issue of Genes & Development, two companion papers (Trakala and colleagues [pp. 1079–1092] and Shoshani and colleagues [pp. 1093–1108]) exploited sophisticated mouse models to study the progression of aneuploidy from early phases to established tumors. Both groups observed that, while in the early nontumor...
Source: Genes and Development - August 2, 2021 Category: Genetics & Stem Cells Authors: Chiarle, R. Tags: Cell Biology, Chromosome Dynamics and Nuclear Architecture, Cancer and Disease Models Outlook Source Type: research
Erratum: Meikin synergizes with shugoshin to protect cohesin Rec8 during meiosis I [Errata]
(Source: Genes and Development)
Source: Genes and Development - July 1, 2021 Category: Genetics & Stem Cells Authors: Ma, W., Zhou, J., Chen, J., Carr, A. M., Watanabe, Y. Tags: Errata Source Type: research
Corrigendum: Differential requirements for MDM2 E3 activity during embryogenesis and in adult mice [Errata]
(Source: Genes and Development)
Source: Genes and Development - July 1, 2021 Category: Genetics & Stem Cells Authors: Humpton, T. J., Nomura, K., Weber, J., Magnussen, H. M., Hock, A. K., Nixon, C., Dhayade, S., Stevenson, D., Huang, D. T., Strathdee, D., Blyth, K., Vousden, K. H. Tags: Errata Source Type: research
Divergent evolution toward sex chromosome-specific gene regulation in Drosophila [Research Papers]
The dosage compensation complex (DCC) of Drosophila identifies its X-chromosomal binding sites with exquisite selectivity. The principles that assure this vital targeting are known from the D. melanogaster model: DCC-intrinsic specificity of DNA binding, cooperativity with the CLAMP protein, and noncoding roX2 RNA transcribed from the X chromosome. We found that in D. virilis, a species separated from melanogaster by 40 million years of evolution, all principles are active but contribute differently to X specificity. In melanogaster, the DCC subunit MSL2 evolved intrinsic DNA-binding selectivity for rare PionX sites, which...
Source: Genes and Development - July 1, 2021 Category: Genetics & Stem Cells Authors: Villa, R., Jagtap, P. K. A., Thomae, A. W., Campos Sparr, A., Forne, I., Hennig, J., Straub, T., Becker, P. B. Tags: Research Papers Source Type: research
