Human pre-mRNA 3' end processing: reconstituting is believing [Outlook]
It is every biochemist's dream to reconstitute a biological process in vitro using defined components, because doing so not only reduces a biological phenomenon to one or a series of biochemical reactions, but also defines the minimal list of essential components. In this issue of Genes & Development, Boreikaite and colleagues (pp. 210–224) and Schmidt and colleagues (pp. 195–209) report their independent reconstitution of human pre-mRNA 3' end processing. (Source: Genes and Development)
Source: Genes and Development - February 22, 2022 Category: Genetics & Stem Cells Authors: Yoon, Y., Shi, Y. Tags: Post-transcriptional Control Outlook Source Type: research
The inner workings of replisome-dependent control of DNA damage tolerance [Outlook]
Genomic DNA is continuously challenged by endogenous and exogenous sources of damage. The resulting lesions may act as physical blocks to DNA replication, necessitating repair mechanisms to be intrinsically coupled to the DNA replisome machinery. DNA damage tolerance (DDT) is comprised of translesion synthesis (TLS) and template switch (TS) repair processes that allow the replisome to bypass of bulky DNA lesions and complete DNA replication. How the replisome orchestrates which DDT repair mechanism becomes active at replication blocks has remained enigmatic. In this issue of Genes & Development, Dolce and colleagues (p...
Source: Genes and Development - February 22, 2022 Category: Genetics & Stem Cells Authors: Zhang, T., Greenberg, R. A. Tags: DNA Recombination and Repair Outlook Source Type: research
Highly rigid H3.1/H3.2-H3K9me3 domains set a barrier for cell fate reprogramming in trophoblast stem cells [Research Papers]
The placenta is a highly evolved, specialized organ in mammals. It differs from other organs in that it functions only for fetal maintenance during gestation. Therefore, there must be intrinsic mechanisms that guarantee its unique functions. To address this question, we comprehensively analyzed epigenomic features of mouse trophoblast stem cells (TSCs). Our genome-wide, high-throughput analyses revealed that the TSC genome contains large-scale (>1-Mb) rigid heterochromatin architectures with a high degree of histone H3.1/3.2–H3K9me3 accumulation, which we termed TSC-defined highly heterochromatinized domains (THDs...
Source: Genes and Development - January 12, 2022 Category: Genetics & Stem Cells Authors: Hada, M., Miura, H., Tanigawa, A., Matoba, S., Inoue, K., Ogonuki, N., Hirose, M., Watanabe, N., Nakato, R., Fujiki, K., Hasegawa, A., Sakashita, A., Okae, H., Miura, K., Shikata, D., Arima, T., Shirahige, K., Hiratani, I., Ogura, A. Tags: Research Papers Source Type: research
Guide RNA acrobatics: positioning consecutive uridines for pseudouridylation by H/ACA pseudouridylation loops with dual guide capacity [Research Papers]
Site-specific pseudouridylation of human ribosomal and spliceosomal RNAs is directed by H/ACA guide RNAs composed of two hairpins carrying internal pseudouridylation guide loops. The distal "antisense" sequences of the pseudouridylation loop base-pair with the target RNA to position two unpaired target nucleotides 5'-UN-3', including the 5' substrate U, under the base of the distal stem topping the guide loop. Therefore, each pseudouridylation loop is expected to direct synthesis of a single pseudouridine () in the target sequence. However, in this study, genetic depletion and restoration and RNA mutational analyses demons...
Source: Genes and Development - January 12, 2022 Category: Genetics & Stem Cells Authors: Jady, B. E., Ketele, A., Moulis, D., Kiss, T. Tags: Research Papers Source Type: research
The Zip4 protein directly couples meiotic crossover formation to synaptonemal complex assembly [Research Papers]
Meiotic recombination is triggered by programmed double-strand breaks (DSBs), a subset of these being repaired as crossovers, promoted by eight evolutionarily conserved proteins, named ZMM. Crossover formation is functionally linked to synaptonemal complex (SC) assembly between homologous chromosomes, but the underlying mechanism is unknown. Here we show that Ecm11, a SC central element protein, localizes on both DSB sites and sites that attach chromatin loops to the chromosome axis, which are the starting points of SC formation, in a way that strictly requires the ZMM protein Zip4. Furthermore, Zip4 directly interacts wit...
Source: Genes and Development - January 12, 2022 Category: Genetics & Stem Cells Authors: Pyatnitskaya, A., Andreani, J., Guerois, R., De Muyt, A., Borde, V. Tags: Research Papers Source Type: research
Transcription factor-mediated intestinal metaplasia and the role of a shadow enhancer [Research Papers]
Barrett's esophagus (BE) and gastric intestinal metaplasia are related premalignant conditions in which areas of human stomach epithelium express mixed gastric and intestinal features. Intestinal transcription factors (TFs) are expressed in both conditions, with unclear causal roles and cis-regulatory mechanisms. Ectopic CDX2 reprogrammed isogenic mouse stomach organoid lines to a hybrid stomach–intestinal state transcriptionally similar to clinical metaplasia; squamous esophageal organoids resisted this CDX2-mediated effect. Reprogramming was associated with induced activity at thousands of previously inaccessible i...
Source: Genes and Development - January 12, 2022 Category: Genetics & Stem Cells Authors: Singh, H., Seruggia, D., Madha, S., Saxena, M., Nagaraja, A. K., Wu, Z., Zhou, J., Huebner, A. J., Maglieri, A., Wezenbeek, J., Hochedlinger, K., Orkin, S. H., Bass, A. J., Hornick, J. L., Shivdasani, R. A. Tags: Research Papers Source Type: research
Functional rejuvenation of aged neural stem cells by Plagl2 and anti-Dyrk1a activity [Research Papers]
The regenerative potential of neural stem cells (NSCs) declines during aging, leading to cognitive dysfunctions. This decline involves up-regulation of senescence-associated genes, but inactivation of such genes failed to reverse aging of hippocampal NSCs. Because many genes are up-regulated or down-regulated during aging, manipulation of single genes would be insufficient to reverse aging. Here we searched for a gene combination that can rejuvenate NSCs in the aged mouse brain from nuclear factors differentially expressed between embryonic and adult NSCs and their modulators. We found that a combination of inducing the zi...
Source: Genes and Development - January 12, 2022 Category: Genetics & Stem Cells Authors: Kaise, T., Fukui, M., Sueda, R., Piao, W., Yamada, M., Kobayashi, T., Imayoshi, I., Kageyama, R. Tags: Research Papers Source Type: research
Functional interaction between the RNA exosome and the sirtuin deacetylase Hst3 maintains transcriptional homeostasis [Research Communications]
Eukaryotic cells maintain an optimal level of mRNAs through unknown mechanisms that balance RNA synthesis and degradation. We found that inactivation of the RNA exosome leads to global reduction of nascent mRNA transcripts, and that this defect is accentuated by loss of deposition of histone variant H2A.Z. We identify the mRNA for the sirtuin deacetylase Hst3 as a key target for the RNA exosome that mediates communication between RNA degradation and transcription machineries. These findings reveal how the RNA exosome and H2A.Z function together to control a deacetylase, ensuring proper levels of transcription in response t...
Source: Genes and Development - January 12, 2022 Category: Genetics & Stem Cells Authors: Bryll, A. R., Peterson, C. L. Tags: Research Communications Source Type: research
The transcription factor activity gradient (TAG) model: contemplating a contact-independent mechanism for enhancer-promoter communication [Perspectives]
How distal cis-regulatory elements (e.g., enhancers) communicate with promoters remains an unresolved question of fundamental importance. Although transcription factors and cofactors are known to mediate this communication, the mechanism by which diffusible molecules relay regulatory information from one position to another along the chromosome is a biophysical puzzle—one that needs to be revisited in light of recent data that cannot easily fit into previous solutions. Here we propose a new model that diverges from the textbook enhancer–promoter looping paradigm and offer a synthesis of the literature to make a...
Source: Genes and Development - January 12, 2022 Category: Genetics & Stem Cells Authors: Karr, J. P., Ferrie, J. J., Tjian, R., Darzacq, X. Tags: Chromatin and Gene Expression Perspectives Source Type: research
Coupling crossover and synaptonemal complex in meiosis [Outlook]
During meiosis, a molecular program induces DNA double-strand breaks (DSBs) and their repair by homologous recombination. DSBs can be repaired with or without crossovers. ZMM proteins promote the repair toward crossover. The sites of DSB repair are also sites where the axes of homologous chromosomes are juxtaposed and stabilized, and where a structure called the synaptonemal complex initiates, providing further regulation of both DSB formation and repair. How crossover formation and synapsis initiation are linked has remained unknown. The study by Pyatnitskaya and colleagues (pp. 53–69) in this issue of Genes & D...
Source: Genes and Development - January 12, 2022 Category: Genetics & Stem Cells Authors: Grey, C., de Massy, B. Tags: DNA Recombination and Repair Outlook Source Type: research
Guide RNA acrobatics: the one-for-two shuffle [Outlook]
RNA modifications are crucial for the proper function of the RNAs. The sites of pseudouridines are often specified by dual hairpin guide RNAs, with one or both hairpins identifying a target uridine. In this issue of Genes & Development, Jády and colleagues (pp. 70–83) identify a novel mechanism by which a single guide RNA hairpin can specify two uridines adjacent to each other or separated by 1 nt; i.e., one for two or guide RNA acrobatics. (Source: Genes and Development)
Source: Genes and Development - January 12, 2022 Category: Genetics & Stem Cells Authors: Meier, U. T. Tags: Methods and Analysis, Post-transcriptional Control Outlook Source Type: research
Reviewers, Volume 35 (2021) [Reviewers]
(Source: Genes and Development)
Source: Genes and Development - December 3, 2021 Category: Genetics & Stem Cells Tags: Reviewers Source Type: research
Corrigendum: In vivo CRISPR screening for phenotypic targets of the mir-35-42 family in C. elegans [Errata]
(Source: Genes and Development)
Source: Genes and Development - December 3, 2021 Category: Genetics & Stem Cells Authors: Yang, B., Schwartz, M., McJunkin, K. Tags: Errata Source Type: research
Recognition of acetylated histone by Yaf9 regulates metabolic cycling of transcription initiation and chromatin regulatory factors [Research Papers]
How transcription programs rapidly adjust to changing metabolic and cellular cues remains poorly defined. Here, we reveal a function for the Yaf9 component of the SWR1-C and NuA4 chromatin regulatory complexes in maintaining timely transcription of metabolic genes across the yeast metabolic cycle (YMC). By reading histone acetylation during the oxidative and respiratory phase of the YMC, Yaf9 recruits SWR1-C and NuA4 complexes to deposit H2A.Z and acetylate H4, respectively. Increased H2A.Z and H4 acetylation during the oxidative phase promotes transcriptional initiation and chromatin machinery occupancy and is associated ...
Source: Genes and Development - December 3, 2021 Category: Genetics & Stem Cells Authors: Zhang, J., Gundu, A., Strahl, B. D. Tags: Research Papers Source Type: research
TBX2 controls a proproliferative gene expression program in melanoma [Research Papers]
Senescence shapes embryonic development, plays a key role in aging, and is a critical barrier to cancer initiation, yet how senescence is regulated remains incompletely understood. TBX2 is an antisenescence T-box family transcription repressor implicated in embryonic development and cancer. However, the repertoire of TBX2 target genes, its cooperating partners, and how TBX2 promotes proliferation and senescence bypass are poorly understood. Here, using melanoma as a model, we show that TBX2 lies downstream from PI3K signaling and that TBX2 binds and is required for expression of E2F1, a key antisenescence cell cycle regula...
Source: Genes and Development - December 3, 2021 Category: Genetics & Stem Cells Authors: Lu, S., Louphrasitthiphol, P., Goradia, N., Lambert, J.-P., Schmidt, J., Chauhan, J., Rughani, M. G., Larue, L., Wilmanns, M., Goding, C. R. Tags: Research Papers Source Type: research
