Nucleolar-based Dux repression is essential for embryonic two-cell stage exit [Research Papers]
Upon fertilization, the mammalian embryo must switch from dependence on maternal transcripts to transcribing its own genome, and in mice this involves the transient up-regulation of MERVL transposons and MERVL-driven genes at the two-cell stage. The mechanisms and requirement for MERVL and two-cell (2C) gene up-regulation are poorly understood. Moreover, this MERVL-driven transcriptional program must be rapidly shut off to allow two-cell exit and developmental progression. Here, we report that robust ribosomal RNA (rRNA) synthesis and nucleolar maturation are essential for exit from the 2C state. 2C-like cells and two-cell...
Source: Genes and Development - March 22, 2022 Category: Genetics & Stem Cells Authors: Xie, S. Q., Leeke, B. J., Whilding, C., Wagner, R. T., Garcia-Llagostera, F., Low, Y., Chammas, P., Cheung, N. T.- F., Dormann, D., McManus, M. T., Percharde, M. Tags: Research Papers Source Type: research
Rap1 regulates TIP60 function during fate transition between two-cell-like and pluripotent states [Research Papers]
In mammals, the conserved telomere binding protein Rap1 serves a diverse set of nontelomeric functions, including activation of the NF-kB signaling pathway, maintenance of metabolic function in vivo, and transcriptional regulation. Here, we uncover the mechanism by which Rap1 modulates gene expression. Using a separation-of-function allele, we show that Rap1 transcriptional regulation is largely independent of TRF2-mediated binding to telomeres and does not involve direct binding to genomic loci. Instead, Rap1 interacts with the TIP60/p400 complex and modulates its histone acetyltransferase activity. Notably, we show that ...
Source: Genes and Development - March 22, 2022 Category: Genetics & Stem Cells Authors: Barry, R. M., Sacco, O., Mameri, A., Stojaspal, M., Kartsonis, W., Shah, P., De Ioannes, P., Hofr, C., Cote, J., Sfeir, A. Tags: Research Papers Source Type: research
Isoform-specific functions of PPAR{gamma} in gene regulation and metabolism [Research Papers]
Peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPAR by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPAR isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPAR1 and PPAR2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPAR1 or PPAR2 to assess isoform-specific gene regulation. Strik...
Source: Genes and Development - March 22, 2022 Category: Genetics & Stem Cells Authors: Hu, W., Jiang, C., Kim, M., Xiao, Y., Richter, H. J., Guan, D., Zhu, K., Krusen, B. M., Roberts, A. N., Miller, J., Steger, D. J., Lazar, M. A. Tags: Research Papers Source Type: research
NDF is a transcription factor that stimulates elongation by RNA polymerase II [Research Communications]
RNA polymerase II (Pol II) elongation is a critical step in gene expression. Here we found that NDF, which was identified as a bilaterian nucleosome-destabilizing factor, is also a Pol II transcription factor that stimulates elongation with plain DNA templates in the absence of nucleosomes. NDF binds directly to Pol II and enhances elongation by a different mechanism than that used by transcription factor TFIIS. Moreover, yeast Pdp3, which is related to NDF, binds to Pol II and stimulates elongation. Thus, NDF is a Pol II binding transcription elongation factor that is localized over gene bodies and is conserved from yeast...
Source: Genes and Development - March 22, 2022 Category: Genetics & Stem Cells Authors: Fei, J., Xu, J., Li, Z., Xu, K., Wang, D., Kassavetis, G. A., Kadonaga, J. T. Tags: Research Communications Source Type: research
DNA repair defects in cancer and therapeutic opportunities [Reviews]
DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to tumorigenesis, but also render cancer cells vulnerable to DNA damage and reliant on remaining repair and signaling activities. Here, we 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. Furthermore, we discuss the impacts of DNA repair defects on both targeted therapy and immunotherapy, and highlight emerging principles for t...
Source: Genes and Development - March 22, 2022 Category: Genetics & Stem Cells Authors: Hopkins, J. L., Lan, L., Zou, L. Tags: DNA Recombination and Repair, Cancer and Disease Models Reviews Source Type: research
Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic [Reviews]
Despite FDA approval of nine new drugs for patients with acute myeloid leukemia (AML) in the United States over the last 4 years, AML remains a major area of unmet medical need among hematologic malignancies. In this review, we 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. In addition, we review progress in immune targeting of AML through anti-CD47, anti-SIRPα, and anti-TIM-3 antibodies; bispecific and trispecific antibodies; and new cellular therapies ...
Source: Genes and Development - March 22, 2022 Category: Genetics & Stem Cells Authors: Bewersdorf, J. P., Abdel-Wahab, O. Tags: Cancer and Disease Models Reviews Source Type: research
Killing SCLC: insights into how to target a shapeshifting tumor [Reviews]
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 ce...
Source: Genes and Development - March 22, 2022 Category: Genetics & Stem Cells Authors: Sutherland, K. D., Ireland, A. S., Oliver, T. G. Tags: Cancer and Disease Models Reviews Source Type: research
Distinct structural bases for sequence-specific DNA binding by mammalian BEN domain proteins [Research Papers]
The BEN domain is a recently recognized DNA binding module that is present in diverse metazoans and certain viruses. Several BEN domain factors are known as transcriptional repressors, but, overall, relatively little is known of how BEN factors identify their targets in humans. In particular, X-ray structures of BEN domain:DNA complexes are only known for Drosophila factors bearing a single BEN domain, which lack direct vertebrate orthologs. Here, we characterize several mammalian BEN domain (BD) factors, including from two NACC family BTB-BEN proteins and from BEND3, which has four BDs. In vitro selection data revealed se...
Source: Genes and Development - February 22, 2022 Category: Genetics & Stem Cells Authors: Zheng, L., Liu, J., Niu, L., Kamran, M., Yang, A. W. H., Jolma, A., Dai, Q., Hughes, T. R., Patel, D. J., Zhang, L., Prasanth, S. G., Yu, Y., Ren, A., Lai, E. C. Tags: Research Papers Source Type: research
RBBP6 activates the pre-mRNA 3' end processing machinery in humans [Research Papers]
3' end processing of most human mRNAs is carried out by the cleavage and polyadenylation specificity factor (CPSF; CPF in yeast). Endonucleolytic cleavage of the nascent pre-mRNA defines the 3' end of the mature transcript, which is important for mRNA localization, translation, and stability. Cleavage must therefore be tightly regulated. Here, we 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 ...
Source: Genes and Development - February 22, 2022 Category: Genetics & Stem Cells Authors: Boreikaite, V., Elliott, T. S., Chin, J. W., Passmore, L. A. Tags: Research Papers Source Type: research
Reconstitution of 3' end processing of mammalian pre-mRNA reveals a central role of RBBP6 [Research Papers]
The 3' ends of almost all eukaryotic mRNAs are generated in an essential two-step processing reaction: endonucleolytic cleavage of an extended precursor followed by the addition of a poly(A) tail. By reconstituting the reaction from overproduced and purified proteins, we provide a minimal list of 14 polypeptides that are essential and two that are stimulatory for RNA processing. In a reaction depending on the polyadenylation signal AAUAAA, the reconstituted system cleaves pre-mRNA at a single preferred site corresponding to the one used in vivo. Among the proteins, cleavage factor I stimulates cleavage but is not essential...
Source: Genes and Development - February 22, 2022 Category: Genetics & Stem Cells Authors: Schmidt, M., Kluge, F., Sandmeir, F., Kühn, U., Schäfer, P., Tüting, C., Ihling, C., Conti, E., Wahle, E. Tags: Research Papers Source Type: research
YTHDC2 control of gametogenesis requires helicase activity but not m6A binding [Research Papers]
Mechanisms regulating meiotic progression in mammals are poorly understood. The N6-methyladenosine (m6A) reader and 3' -> 5' RNA helicase YTHDC2 switches cells from mitotic to meiotic gene expression programs and is essential for meiotic entry, but how this critical cell fate change is accomplished is unknown. Here, we provide insight into its mechanism and implicate YTHDC2 in having a broad role in gene regulation during multiple meiotic stages. Unexpectedly, mutation of the m6A-binding pocket of YTHDC2 had no detectable effect on gametogenesis and mouse fertility, suggesting that YTHDC2 function is m6A-independent. Su...
Source: Genes and Development - February 22, 2022 Category: Genetics & Stem Cells Authors: Saito, Y., Hawley, B. R., Puno, M. R., Sarathy, S. N., Lima, C. D., Jaffrey, S. R., Darnell, R. B., Keeney, S., Jain, D. Tags: Research Papers Source Type: research
Parental histone deposition on the replicated strands promotes error-free DNA damage tolerance and regulates drug resistance [Research Papers]
Ctf4 is a conserved replisome component with multiple roles in DNA metabolism. To investigate connections between Ctf4-mediated processes involved in drug resistance, we conducted a suppressor screen of ctf4 sensitivity to the methylating agent MMS. We uncovered that mutations in Dpb3 and Dpb4 components of polymerase result in the development of drug resistance in ctf4 via their histone-binding function. Alleviated sensitivity to MMS of the double mutants was not associated with rescue of ctf4 defects in sister chromatid cohesion, replication fork architecture, or template switching, which ensures error-free replication i...
Source: Genes and Development - February 22, 2022 Category: Genetics & Stem Cells Authors: Dolce, V., Dusi, S., Giannattasio, M., Joseph, C. R., Fumasoni, M., Branzei, D. Tags: Research Papers Source Type: research
BMAL1 drives muscle repair through control of hypoxic NAD+ regeneration in satellite cells [Research Papers]
The process of tissue regeneration occurs in a developmentally timed manner, yet the role of circadian timing is not understood. Here, we identify a role for the adult muscle stem cell (MuSC)-autonomous clock in the control of muscle regeneration following acute ischemic injury. We observed greater muscle repair capacity following injury during the active/wake period as compared with the inactive/rest period in mice, and loss of Bmal1 within MuSCs leads to impaired muscle regeneration. We demonstrate that Bmal1 loss in MuSCs leads to reduced activated MuSC number at day 3 postinjury, indicating a failure to properly expand...
Source: Genes and Development - February 22, 2022 Category: Genetics & Stem Cells Authors: Zhu, P., Hamlish, N. X., Thakkar, A. V., Steffeck, A. W. T., Rendleman, E. J., Khan, N. H., Waldeck, N. J., DeVilbiss, A. W., Martin-Sandoval, M. S., Mathews, T. P., Chandel, N. S., Peek, C. B. Tags: Research Papers Source Type: research
Macrophages facilitate peripheral nerve regeneration by organizing regeneration tracks through Plexin-B2 [Research Papers]
The regeneration of peripheral nerves is guided by regeneration tracks formed through an interplay of many cell types, but the underlying signaling pathways remain unclear. Here, we 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 nerves. Conditional deletion of Plexin-B2 in myeloid lineage resulted in not only macrophage misalignment but also matrix disarray and Schwann cell disorganizat...
Source: Genes and Development - February 22, 2022 Category: Genetics & Stem Cells Authors: Li, Y., Kang, S., Halawani, D., Wang, Y., Junqueira Alves, C., Ramakrishnan, A., Estill, M., Shen, L., Li, F., He, X., Friedel, R. H., Zou, H. Tags: Research Papers Source Type: research
Minding the message: tactics controlling RNA decay, modification, and translation in virus-infected cells [Reviews]
With their categorical requirement for host ribosomes to translate mRNA, viruses provide a wealth of genetically tractable models to investigate how gene expression is remodeled post-transcriptionally by infection-triggered biological stress. By co-opting and subverting cellular pathways that control mRNA decay, modification, and translation, the global landscape of post-transcriptional processes is swiftly reshaped by virus-encoded factors. Concurrent host cell-intrinsic countermeasures likewise conscript post-transcriptional strategies to mobilize critical innate immune defenses. Here we review strategies and mechanisms ...
Source: Genes and Development - February 22, 2022 Category: Genetics & Stem Cells Authors: Burgess, H. M., Vink, E. I., Mohr, I. Tags: Bacteria and Viruses, Translation, Post-transcriptional Control Reviews Source Type: research
