Dynamic nucleosome remodeling mediated by YY1 underlies early mouse development [Research Papers]
In this study, using a low-input MNase-seq method, we show that nucleosome positioning is globally obscure in zygotes but becomes well defined during subsequent development. Down-regulation of the chromatin assembly in embryonic stem cells can partially reverse nucleosome organization into a zygote-like pattern, suggesting a possible link between the chromatin assembly pathway and fuzzy nucleosomes in zygotes. We also reveal that YY1, a zinc finger-containing transcription factor expressed upon zygotic genome activation, regulates the de novo formation of well-positioned nucleosome arrays at the regulatory elements through...
Source: Genes and Development - August 17, 2023 Category: Genetics & Stem Cells Authors: Sakamoto, M., Abe, S., Miki, Y., Miyanari, Y., Sasaki, H., Ishiuchi, T. Tags: Research Papers Source Type: research
Histone bivalency regulates the timing of cerebellar granule cell development [Research Papers]
Developing neurons undergo a progression of morphological and gene expression changes as they transition from neuronal progenitors to mature neurons. Here we used RNA-seq and H3K4me3 and H3K27me3 ChIP-seq to analyze how chromatin modifications control gene expression in a specific type of CNS neuron: the mouse cerebellar granule cell (GC). We found that in proliferating GC progenitors (GCPs), H3K4me3/H3K27me3 bivalency is common at neuronal genes and undergoes dynamic changes that correlate with gene expression during migration and circuit formation. Expressing a fluorescent sensor for bivalent domains revealed subnuclear ...
Source: Genes and Development - August 17, 2023 Category: Genetics & Stem Cells Authors: Mätlik, K., Govek, E.-E., Paul, M. R., Allis, C. D., Hatten, M. E. Tags: Research Papers Source Type: research
CST-Pol{alpha}/Primase: the second telomere maintenance machine [Reviews]
It has been known for decades that telomerase extends the 3' end of linear eukaryotic chromosomes and dictates the telomeric repeat sequence based on the template in its RNA. However, telomerase does not mitigate sequence loss at the 5' ends of chromosomes, which results from lagging strand DNA synthesis and nucleolytic processing. Therefore, a second enzyme is needed to keep telomeres intact: DNA polymerase α/Primase bound to Ctc1–Stn1–Ten1 (CST). CST–Polα/Primase maintains telomeres through a fill-in reaction that replenishes the lost sequences at the 5' ends. CST not only serves to maintain...
Source: Genes and Development - August 17, 2023 Category: Genetics & Stem Cells Authors: Cai, S. W., de Lange, T. Tags: Cell Cycle and DNA Replication, Chromatin and Gene Expression Reviews Source Type: research
Evolutionary conservation of the structure and function of meiotic Rec114-Mei4 and Mer2 complexes [Research Papers]
Meiosis-specific Rec114–Mei4 and Mer2 complexes are thought to enable Spo11-mediated DNA double-strand break (DSB) formation through a mechanism that involves DNA-dependent condensation. However, the structure, molecular properties, and evolutionary conservation of Rec114–Mei4 and Mer2 are unclear. Here, we present AlphaFold models of Rec114–Mei4 and Mer2 complexes supported by nuclear magnetic resonance (NMR) spectroscopy, small-angle X-ray scattering (SAXS), and mutagenesis. We show that dimers composed of the Rec114 C terminus form α-helical chains that cup an N-terminal Mei4 α helix, and t...
Source: Genes and Development - July 18, 2023 Category: Genetics & Stem Cells Authors: Daccache, D., De Jonge, E., Liloku, P., Mechleb, K., Haddad, M., Corthaut, S., Sterckx, Y. G.- J., Volkov, A. N., Claeys Bouuaert, C. Tags: Research Papers Source Type: research
Structure and DNA-bridging activity of the essential Rec114-Mei4 trimer interface [Research Papers]
The DNA double-strand breaks (DSBs) that initiate meiotic recombination are formed by an evolutionarily conserved suite of factors that includes Rec114 and Mei4 (RM), which regulate DSB formation both spatially and temporally. In vivo, these proteins form large immunostaining foci that are integrated with higher-order chromosome structures. In vitro, they form a 2:1 heterotrimeric complex that binds cooperatively to DNA to form large, dynamic condensates. However, understanding of the atomic structures and dynamic DNA binding properties of RM complexes is lacking. Here, we report a structural model of a heterotrimeric comp...
Source: Genes and Development - July 18, 2023 Category: Genetics & Stem Cells Authors: Liu, K., Grasso, E. M., Pu, S., Zou, M., Liu, S., Eliezer, D., Keeney, S. Tags: Research Papers Source Type: research
Nuclear mRNPs are compact particles packaged with a network of proteins promoting RNA-RNA interactions [Research Papers]
Messenger RNAs (mRNAs) are at the center of the central dogma of molecular biology. In eukaryotic cells, these long ribonucleic acid polymers do not exist as naked transcripts; rather, they associate with mRNA-binding proteins to form messenger ribonucleoprotein (mRNP) complexes. Recently, global proteomic and transcriptomic studies have provided comprehensive inventories of mRNP components. However, knowledge of the molecular features of distinct mRNP populations has remained elusive. We purified endogenous nuclear mRNPs from Saccharomyces cerevisiae by harnessing the mRNP biogenesis factors THO and Sub2 in biochemical pr...
Source: Genes and Development - July 18, 2023 Category: Genetics & Stem Cells Authors: Bonneau, F., Basquin, J., Steigenberger, B., Schäfer, T., Schäfer, I. B., Conti, E. Tags: Research Papers Source Type: research
Major {beta} cell-specific functions of NKX2.2 are mediated via the NK2-specific domain [Research Papers]
In this study, we demonstrate that β cell-specific functions of NKX2.2 are driven by the highly conserved NK2-specific domain (SD). Mutation of the endogenous NKX2.2 SD prevents the developmental progression of β cell precursors into mature, insulin-expressing β cells, resulting in overt neonatal diabetes. Within the adult β cell, the SD stimulates β cell performance through the activation and repression of a subset of NKX2.2-regulated transcripts critical for β cell function. These irregularities in β cell gene expression may be mediated via SD-contingent interactions with components of ...
Source: Genes and Development - July 18, 2023 Category: Genetics & Stem Cells Authors: Abarinov, V., Levine, J. A., Churchill, A. J., Hopwood, B., Deiter, C. S., Guney, M. A., Wells, K. L., Schrunk, J. M., Guo, Y., Hammelman, J., Gifford, D. K., Magnuson, M. A., Wichterle, H., Sussel, L. Tags: Research Papers Source Type: research
Translational regulation by uORFs and start codon selection stringency [Reviews]
In addition to the main, protein-coding, open reading frame (mORF), many eukaryotic mRNAs contain upstream ORFs (uORFs) initiated at AUG or near-cognate codons residing 5' of the mORF start site. Whereas translation of uORFs generally represses translation of the mORFs, a subset of uORFs serves as a nexus for regulating translation of the mORF. In this review, we summarize the mechanisms by which uORFs can repress or stimulate mRNA translation, highlight uORF-mediated translational repression involving ribosome queuing, and critically evaluate recently described alternatives to the delayed reinitiation model for uORF-media...
Source: Genes and Development - July 18, 2023 Category: Genetics & Stem Cells Authors: Dever, T. E., Ivanov, I. P., Hinnebusch, A. G. Tags: Translation Reviews Source Type: research
Circadian mechanisms in adipose tissue bioenergetics and plasticity [Reviews]
The circadian clock plays an essential role in coordinating feeding and metabolic rhythms with the light/dark cycle. Disruption of clocks is associated with increased adiposity and metabolic disorders, whereas aligning feeding time with cell-autonomous rhythms in metabolism improves health. Here, we provide a comprehensive overview of recent literature in adipose tissue biology as well as our understanding of molecular mechanisms underlying the circadian regulation of transcription, metabolism, and inflammation in adipose tissue. We highlight recent efforts to uncover the mechanistic links between clocks and adipocyte meta...
Source: Genes and Development - July 18, 2023 Category: Genetics & Stem Cells Authors: Hepler, C., Bass, J. Tags: Molecular Physiology and Metabolism Reviews Source Type: research
Differential use of the Nkx2.2 NK2 domain in developing pancreatic islets and neurons [Outlook]
The homeodomain transcription factor (TF) Nkx2.2 governs crucial cell fate decisions in several developing organs, including the central nervous system (CNS), pancreas, and intestine. How Nkx2.2 regulates unique targets in these different systems to impact their individual transcriptional programs remains unclear. In this issue of Genes & Development Abarinov and colleagues (pp. 490–504) generated and analyzed mice in which the Nkx2.2 SD is mutated and found that the SD is required for normal pancreatic islet differentiation but dispensable for most aspects of neuronal differentiation. (Source: Genes and Development)
Source: Genes and Development - July 18, 2023 Category: Genetics & Stem Cells Authors: Seymour, P. A., Serup, P. Tags: Development, Chromatin and Gene Expression Outlook Source Type: research
Corrigendum: Hierarchical reactivation of transcription during mitosis-to-G1 transition by Brn2 and Ascl1 in neural stem cells [Errata]
(Source: Genes and Development)
Source: Genes and Development - June 5, 2023 Category: Genetics & Stem Cells Authors: Soares, M. A. F., Soares, D. S., Teixeira, V., Heskol, A., Bressan, R. B., Pollard, S. M., Oliveira, R. A., Castro, D. S. Tags: Errata Source Type: research
Butt-seq: a new method for facile profiling of transcription [Resource/Methodology]
A wide range of sequencing methods has been developed to assess nascent RNA transcription and resolve the single-nucleotide position of RNA polymerase genome-wide. These techniques are often burdened with high input material requirements and lengthy protocols. We leveraged the template-switching properties of thermostable group II intron reverse transcriptase (TGIRT) and developed Butt-seq (bulk analysis of nascent transcript termini sequencing), which can produce libraries from purified nascent RNA in 6 h and from as few as 10,000 cells—an improvement of at least 10-fold over existing techniques. Butt-seq shows that...
Source: Genes and Development - June 5, 2023 Category: Genetics & Stem Cells Authors: Yu, A. D., Rosbash, M. Tags: Resource/Methodology Source Type: research
Germ cell-specific eIF4E1b regulates maternal mRNA translation to ensure zygotic genome activation [Research Papers]
Translation of maternal mRNAs is detected before transcription of zygotic genes and is essential for mammalian embryo development. How certain maternal mRNAs are selected for translation instead of degradation and how this burst of translation affects zygotic genome activation remain unknown. Using gene-edited mice, we document that the oocyte-specific eukaryotic translation initiation factor 4E family member 1b (eIF4E1b) is the regulator of maternal mRNA expression that ensures subsequent reprogramming of the zygotic genome. In oocytes, eIF4E1b binds to transcripts encoding translation machinery proteins, chromatin remode...
Source: Genes and Development - June 5, 2023 Category: Genetics & Stem Cells Authors: Yang, G., Xin, Q., Feng, I., Wu, D., Dean, J. Tags: Research Papers Source Type: research
Long ant life span is maintained by a unique heat shock factor [Research Papers]
Eusocial insect reproductive females show strikingly longer life spans than nonreproductive female workers despite high genetic similarity. In the ant Harpegnathos saltator (Hsal), workers can transition to reproductive "gamergates," acquiring a fivefold prolonged life span by mechanisms that are poorly understood. We found that gamergates have elevated expression of heat shock response (HSR) genes in the absence of heat stress and enhanced survival with heat stress. This HSR gene elevation is driven in part by gamergate-specific up-regulation of the gene encoding a truncated form of a heat shock factor most similar to mam...
Source: Genes and Development - June 5, 2023 Category: Genetics & Stem Cells Authors: Glastad, K. M., Roessler, J., Gospocic, J., Bonasio, R., Berger, S. L. Tags: Research Papers Source Type: research
Role of the proline-rich disordered domain of DROSHA in intronic microRNA processing [Research Papers]
DROSHA serves as a gatekeeper of the microRNA (miRNA) pathway by processing primary transcripts (pri-miRNAs). While the functions of structured domains of DROSHA have been well documented, the contribution of N-terminal proline-rich disordered domain (PRD) remains elusive. Here we show that the PRD promotes the processing of miRNA hairpins located within introns. We identified a DROSHA isoform (p140) lacking the PRD, which is produced by proteolytic cleavage. Small RNA sequencing revealed that p140 is significantly impaired in the maturation of intronic miRNAs. Consistently, our minigene constructs demonstrated that PRD en...
Source: Genes and Development - June 5, 2023 Category: Genetics & Stem Cells Authors: Son, S., Kim, B., Yang, J., Kim, V. N. Tags: Research Papers Source Type: research
