Corrigendum: Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication [Errata]
(Source: Genes and Development)
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Lazzerini Denchi, E., Celli, G., de Lange, T. Tags: Errata Source Type: research

Integrated loss- and gain-of-function screens define a core network governing human embryonic stem cell behavior [Resource/Methodology]
Understanding the genetic control of human embryonic stem cell function is foundational for developmental biology and regenerative medicine. Here we describe an integrated genome-scale loss- and gain-of-function screening approach to identify genetic networks governing embryonic stem cell proliferation and differentiation into the three germ layers. We identified a deep link between pluripotency maintenance and survival by showing that genetic alterations that cause pluripotency dissolution simultaneously increase apoptosis resistance. We discovered that the chromatin-modifying complex SAGA and in particular its subunit TA...
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Naxerova, K., Di Stefano, B., Makofske, J. L., Watson, E. V., de Kort, M. A., Martin, T. D., Dezfulian, M., Ricken, D., Wooten, E. C., Kuroda, M. I., Hochedlinger, K., Elledge, S. J. Tags: Resource/Methodology Source Type: research

Dynamics in Fip1 regulate eukaryotic mRNA 3' end processing [Research Papers]
Cleavage and polyadenylation factor (CPF/CPSF) is a multiprotein complex essential for mRNA 3' end processing in eukaryotes. It contains an endonuclease that cleaves pre-mRNAs, and a polymerase that adds a poly(A) tail onto the cleaved 3' end. Several CPF subunits, including Fip1, contain intrinsically disordered regions (IDRs). IDRs within multiprotein complexes can be flexible, or can become ordered upon interaction with binding partners. Here, we show that yeast Fip1 anchors the poly(A) polymerase Pap1 onto CPF via an interaction with zinc finger 4 of another CPF subunit, Yth1. We also reconstitute a fully recombinant 8...
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Kumar, A., Yu, C. W. H., Rodriguez-Molina, J. B., Li, X.-H., Freund, S. M. V., Passmore, L. A. Tags: Research Papers Source Type: research

Sequential in cis mutagenesis in vivo reveals various functions for CTCF sites at the mouse HoxD cluster [Research Papers]
We examined this possibility by producing an allelic series of cumulative in cis mutations in these sites, up to the abrogation of CTCF binding in the five sites located on one side of the TAD border. In the most impactful alleles, the global chromatin architecture of the locus was modified, yet not drastically, illustrating that CTCF sites located on one side of a strong TAD border are sufficient to organize at least part of this insulation. Spatial colinearity in the expression of these genes along the major body axis was nevertheless maintained, despite abnormal expression boundaries. In contrast, strong effects were sc...
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Amandio, A. R., Beccari, L., Lopez-Delisle, L., Mascrez, B., Zakany, J., Gitto, S., Duboule, D. Tags: Research Papers Source Type: research

Efficient hemogenic endothelial cell specification by RUNX1 is dependent on baseline chromatin accessibility of RUNX1-regulated TGF{beta} target genes [Research Papers]
Hematopoietic stem and progenitor cells (HSPCs) are generated de novo in the embryo from hemogenic endothelial cells (HECs) via an endothelial-to-hematopoietic transition (EHT) that requires the transcription factor RUNX1. Ectopic expression of RUNX1 alone can efficiently promote EHT and HSPC formation from embryonic endothelial cells (ECs), but less efficiently from fetal or adult ECs. Efficiency correlated with baseline accessibility of TGFβ-related genes associated with endothelial-to-mesenchymal transition (EndoMT) and participation of AP-1 and SMAD2/3 to initiate further chromatin remodeling along with RUNX1 at t...
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Howell, E. D., Yzaguirre, A. D., Gao, P., Lis, R., He, B., Lakadamyali, M., Rafii, S., Tan, K., Speck, N. A. Tags: Research Papers Source Type: research

ZFP423 controls EBF2 coactivator recruitment and PPAR{gamma} occupancy to determine the thermogenic plasticity of adipocytes [Research Papers]
Energy-storing white adipocytes maintain their identity by suppressing the energy-burning thermogenic gene program of brown and beige adipocytes. Here, we reveal that the protein–protein interaction between the transcriptional coregulator ZFP423 and brown fat determination factor EBF2 is essential for restraining the thermogenic phenotype of white adipose tissue (WAT). Disruption of the ZFP423–EBF2 protein interaction through CRISPR–Cas9 gene editing triggers widespread "browning" of WAT in adult mice. Mechanistically, ZFP423 recruits the NuRD corepressor complex to EBF2-bound thermogenic gene enhancers. ...
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Shao, M., Zhang, Q., Truong, A., Shan, B., Vishvanath, L., Li, L., Seale, P., Gupta, R. K. Tags: Research Papers Source Type: research

CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum [Research Papers]
Joubert syndrome (JS) is a recessive ciliopathy in which all affected individuals have congenital cerebellar vermis hypoplasia. Here, we report that CEP120, a JS-associated protein involved in centriole biogenesis and cilia assembly, regulates timely neuronal differentiation and the departure of granule neuron progenitors (GNPs) from their germinal zone during cerebellar development. Our results show that depletion of Cep120 perturbs GNP cell cycle progression, resulting in a delay of cell cycle exit in vivo. To dissect the potential mechanism, we investigated the association between CEP120 interactome and the JS database ...
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Chang, C.-H., Chen, T.-Y., Lu, I.-L., Li, R.-B., Tsai, J.-J., Lin, P.-Y., Tang, T. K. Tags: Research Papers Source Type: research

Neural stem/precursor cells dynamically change their epigenetic landscape to differentially respond to BMP signaling for fate switching during brain development [Research Papers]
During neocortical development, tight regulation of neurogenesis-to-astrogenesis switching of neural precursor cells (NPCs) is critical to generate a balanced number of each neural cell type for proper brain functions. Accumulating evidence indicates that a complex array of epigenetic modifications and the availability of extracellular factors control the timing of neuronal and astrocytic differentiation. However, our understanding of NPC fate regulation is still far from complete. Bone morphogenetic proteins (BMPs) are renowned as cytokines that induce astrogenesis of gliogenic late-gestational NPCs. They also promote neu...
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Katada, S., Takouda, J., Nakagawa, T., Honda, M., Igarashi, K., Imamura, T., Ohkawa, Y., Sato, S., Kurumizaka, H., Nakashima, K. Tags: Research Papers Source Type: research

Sentinels of chromatin: chromodomain helicase DNA-binding proteins in development and disease [Reviews]
Chromatin is highly dynamic, undergoing continuous global changes in its structure and type of histone and DNA modifications governed by processes such as transcription, repair, replication, and recombination. Members of the chromodomain helicase DNA-binding (CHD) family of enzymes are ATP-dependent chromatin remodelers that are intimately involved in the regulation of chromatin dynamics, altering nucleosomal structure and DNA accessibility. Genetic studies in yeast, fruit flies, zebrafish, and mice underscore essential roles of CHD enzymes in regulating cellular fate and identity, as well as proper embryonic development. ...
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Alendar, A., Berns, A. Tags: Chromosome Dynamics and Nuclear Architecture, Chromatin and Gene Expression, Cancer and Disease Models Reviews Source Type: research

Dissecting CTCF site function in a tense HoxD locus [Outlook]
In this issue of Genes & Development, Amândio and colleagues (pp. 1490–1509) dissect the function of a cluster of several CTCF binding sites in the HoxD cluster by iterative deletions in mice. They found additive functions for some, and intriguingly found that some sites function as insulators, while others function as anchors for enhancer–promoter interactions. These functions vary depending on developmental context. The work provides new insights into the roles played by CTCF in regulating developmental patterns and 3D chromatin organization. (Source: Genes and Development)
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Bruneau, B. G. Tags: Development, Chromatin and Gene Expression Outlook Source Type: research

Opening the window for endothelial-to-hematopoietic transition [Outlook]
Definitive long-term hematopoietic stem cells (LT-HSCs) arise during embryogenesis in a process termed endothelial-to-hematopoietic transition (EHT), in which specialized hemogenic endothelial cells (HECs) transform into hematopoietic cells. The transcription factor RUNX1 marks HECs and is essential for EHT. Ectopic RUNX1 expression in non-HECs is sufficient to convert them into HECs. However, the conversion efficiency depends on the developmental timing of expression. In this issue of Genes & Development, Howell and colleagues (pp. 1475–1489) leverage this observation to further understand how RUNX1 mediates EHT...
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Samarakkody, A. S., Cantor, A. B. Tags: Development, Stem & Progenitor Cells, Immunology Outlook Source Type: research

Unraveling the complexity of thermogenic remodeling of white fat reveals potential antiobesity therapies [Outlook]
Adipose tissue is a complex organ consisting of a mixture of mature adipocytes and stromal vascular cells. It displays a remarkable ability to adapt to environmental and dietary cues by changing its morphology and metabolic capacity. This plasticity is demonstrated by the emergence of interspersed thermogenic beige adipocytes within white depots in response to catecholamines secretion. Coordinated cellular interaction between different cell types within the tissue and a fine-tuned transcriptional program synergistically take place to promote beige remodeling. However, both cell–cell interactions and molecular mechani...
Source: Genes and Development - November 1, 2021 Category: Genetics & Stem Cells Authors: Rabhi, N., Farmer, S. R. Tags: Molecular Physiology and Metabolism Outlook Source Type: research

Systematic functional characterization of antisense eRNA of protocadherin {alpha} composite enhancer [Research Papers]
Enhancers generate bidirectional noncoding enhancer RNAs (eRNAs) that may regulate gene expression. At present, the eRNA function remains enigmatic. Here, we report a 5' capped antisense eRNA PEARL (Pcdh eRNA associated with R-loop formation) that is transcribed from the protocadherin (Pcdh) α HS5-1 enhancer region. Through loss- and gain-of-function experiments with CRISPR/Cas9 DNA fragment editing, CRISPRi, and CRISPRa, as well as locked nucleic acid strategies, in conjunction with ChIRP, MeDIP, DRIP, QHR-4C, and HiChIP experiments, we found that PEARL regulates Pcdhα gene expression by forming local RNA&ndas...
Source: Genes and Development - October 1, 2021 Category: Genetics & Stem Cells Authors: Zhou, Y., Xu, S., Zhang, M., Wu, Q. Tags: Research Papers Source Type: research

Vertebrate CTF18 and DDX11 essential function in cohesion is bypassed by preventing WAPL-mediated cohesin release [Research Papers]
The alternative PCNA loader containing CTF18-DCC1-CTF8 facilitates sister chromatid cohesion (SCC) by poorly defined mechanisms. Here we found that in DT40 cells, CTF18 acts complementarily with the Warsaw breakage syndrome DDX11 helicase in mediating SCC and proliferation. We uncover that the lethality and cohesion defects of ctf18 ddx11 mutants are associated with reduced levels of chromatin-bound cohesin and rescued by depletion of WAPL, a cohesin-removal factor. On the contrary, high levels of ESCO1/2 acetyltransferases that acetylate cohesin to establish SCC do not rescue ctf18 ddx11 phenotypes. Notably, the tight pro...
Source: Genes and Development - October 1, 2021 Category: Genetics & Stem Cells Authors: Kawasumi, R., Abe, T., Psakhye, I., Miyata, K., Hirota, K., Branzei, D. Tags: Research Papers Source Type: research

Role of 53BP1 in end protection and DNA synthesis at DNA breaks [Research Papers]
Double-strand break (DSB) repair choice is greatly influenced by the initial processing of DNA ends. 53BP1 limits the formation of recombinogenic single-strand DNA (ssDNA) in BRCA1-deficient cells, leading to defects in homologous recombination (HR). However, the exact mechanisms by which 53BP1 inhibits DSB resection remain unclear. Previous studies have identified two potential pathways: protection against DNA2/EXO1 exonucleases presumably through the Shieldin (SHLD) complex binding to ssDNA, and localized DNA synthesis through the CTC1-STN1-TEN1 (CST) and DNA polymerase α (Polα) to counteract resection. Using...
Source: Genes and Development - October 1, 2021 Category: Genetics & Stem Cells Authors: Paiano, J., Zolnerowich, N., Wu, W., Pavani, R., Wang, C., Li, H., Zheng, L., Shen, B., Sleckman, B. P., Chen, B.-R., Nussenzweig, A. Tags: Research Papers Source Type: research