Eukaryotic cells have a layer of heterochromatin at the nuclear periphery. To investigate mechanisms regulating chromatin distribution, we analyzed heterochromatin organization in different tissues and species, including mice with mutations in the lamin B receptor (Lbr) and lamin A (Lmna) genes that encode nuclear envelope (NE) proteins. We identified LBR- and lamin-A/C-dependent mechanisms tethering heterochromatin to the NE. The two tethers are sequentially used during cellular differentiation and development: first the LBR- and then the lamin-A/C-dependent tether. The absence of both LBR and lamin A/C leads to loss of peripheral heterochromatin and an inverted architecture with heterochromatin localizing to the nuclear interior. Myoblast transcriptome analyses indicated that selective disruption of the LBR- or lamin-A-dependent heterochromatin tethers have opposite effects on muscle gene expression, either increasing or decreasing, respectively. These results show how changes in NE composition contribute to regulating heterochromatin positioning, gene expression, and cellular differentiation during development.

Arakawa et al. discovered that the autoimmune response in psoriasis is directed against melanocytes. They show that the main psoriasis risk allele HLA-C*06:02 mediates melanocyte-specific autoimmunity and identify ADAMTSL5 as a melanocyte autoantigen, which stimulates IL-17 and IFN-γ production in CD8+ T cells.

PERK 1,2 . By contrast, the effects of CDDO on CHOP were not blunted by any individual EIF2α kinase deficiency (Extended Data Fig. 1g) , possibly owing to the limited specificity of related compounds 11 . The comparative interrogation of CHOP regulators following three distinct cellular insults allowed us to differentiate global regulators of CHOP biology (Extended Data Fig. 1h-m) from such selectively operating in the context of CCCP-induced mitochondrial depolarization (Extended Data Figs. 2-4). In particular, stringent filtering for genes that prominently scored with CCCP, but not TM or CDDO, highlighted the transcriptional regulators TAF4 and GABPB1, glycolysis factors SLC2A1 and TPI1, and RNA binding proteins RBM27 and CLUH (KIAA0664). Moreover, the signature contained the mitochondrial proteins ATP5IF1 (ATPIF1) and OMA1. Most strikingly, it revealed a strong requirement for HRI (EIF2AK1) and the scarcely studied protein DELE1 (KIAA0141) (Fig. 1a, Extended Data Fig. 5a-b). Cellular dynamics of DELE1Given the scant knowledge on DELE1 and the unexpected involvement of HRI, we first sought to validate their requirement in a panel of cell systems including non-transformed cells, and indeed could confirm their importance in all cases (Extended Data Fig. 5c). Furthermore, CHOP induction also depended on DELE1 and HRI for other types of mitochondrial stress, including inhibition of complex V (oligomycin), TRAP1 (GTPP), and genetic ablation of LONP1 (Extended Data Fig. 5d-f). Failure to induce CHOP after stimulation with CCCP was preceded by a defect in EIF2α phosphorylation in HRI-or DELE1-deficient cells, suggesting that like HRI, DELE1 operates upstream of this event (Extended Data Fig. 5g). Strikingly, expression of HRI in DELE1 knockout cells was able to partially restore CHOP induction, whereas DELE1 expression in HRI-deficient cells was unproductive (Fig. 2a, Extended Data Fig. 6a-b). This indicated that DELE1 requires HRI to trigger CHOP but not vice versa, suggesting that DELE1 may act upstream of both EIF2α and HRI. Given that DELE1 is a mitochondrial protein 12 (Extended Data Fig. 6c), whereas HRI resides in the cytoplasm, we next wondered whether the activity of DELE1 towards HRI might be regulated by its localization. To test this hypothesis, we investigated if artificially rerouting DELE1 to the cytosol would bypass the need for a mitochondrial insult to provoke CHOP expression. Indeed, expression of a DELE1 mutant lacking the mitochondrial targeting sequence (DELE1 ∆MTS ) yielded a predominantly cytoplasmic protein that readily induced CHOP expression independently of CCCP (Fig. 2b-c, Extended Data Fig. 6d-e). This constitutively active version of DELE1 still required HRI to induce CHOP, underscoring its likely role as an activator of HRI. Based on these findings, we asked whether the activity of wild-type DELE1 might be regulated via a similar mechanism. Indeed, while DELE1 localized to mitochondria in unperturbed cells, it could be detected in the cytosol upon CCCP treatment (Fig. 2d). We did not ob...

During maternal-to-embryonic transition control of embryonic development gradually switches from maternal RNAs and proteins stored in the oocyte to gene products generated after embryonic genome activation (EGA). Detailed insight into the onset of embryonic transcription is obscured by the presence of maternal transcripts. Using the bovine model system, we established by RNA sequencing a comprehensive catalogue of transcripts in germinal vesicle and metaphase II oocytes, and in embryos at the four-cell, eight-cell, 16-cell, and blastocyst stages. These were produced by in vitro fertilization of Bos taurus taurus oocytes with sperm from a Bos taurus indicus bull to facilitate parent-specific transcriptome analysis. Transcripts from 12.4 to 13.7 × 10 3 different genes were detected in the various developmental stages. EGA was analyzed by (i) detection of embryonic transcripts, which are not present in oocytes; (ii) detection of transcripts from the paternal allele; and (iii) detection of primary transcripts with intronic sequences. These strategies revealed (i) 220, (ii) 937, and (iii) 6,848 genes to be activated from the four-cell to the blastocyst stage. The largest proportion of gene activation [i.e., (i) 59%, (ii) 42%, and (iii) 58%] was found in eight-cell embryos, indicating major EGA at this stage. Gene ontology analysis of genes activated at the four-cell stage identified categories related to RNA processing, translation, and transport, consistent with preparation for major EGA. Our study provides the largest transcriptome data set of bovine oocyte maturation and early embryonic development and detailed insight into the timing of embryonic activation of specific genes.

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