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In the conventional model of transcriptional activation, transcription factors bind to response elements and recruit co-factors, including histone acetyltransferases. Contrary to this model, we show that the histone acetyltransferase KAT7 (HBO1/MYST2) is required genome wide for histone H3 lysine 14 acetylation (H3K14ac). Examining neural stem cells, we find that KAT7 and H3K14ac are present not only at transcribed genes but also at inactive genes, intergenic regions, and in heterochromatin. KAT7 and H3K14ac were not required for the continued transcription of genes that were actively transcribed at the time of loss of KAT7 but indispensable for the activation of repressed genes. The absence of KAT7 abrogates neural stem cell plasticity, diverse differentiation pathways, and cerebral cortex development. Re-expression of KAT7 restored stem cell developmental potential. Overexpression of KAT7 enhanced neuron and oligodendrocyte differentiation. Our data suggest that KAT7 prepares chromatin for transcriptional activation and is a prerequisite for gene activation. [Display omitted] • KAT7 is essential for H3K14 acetylation, neuron, and oligodendrocyte differentiation • KAT7 and H3K14ac are distributed widely in the genome, including in H3K9me3+ domains • Neuronal gene expression program fails to be activated in the absence of KAT7 • KAT7 creates a permissive chromatin state for transcriptional activation The role of acetylation of specific histone lysine residues remains unclear. Kueh et al. find that the absence of the lysine acetyltransferase KAT7 in neural stem cells causes loss of H3K14 acetylation, a failure to activate the neuron differentiation gene expression program, and neuronal differentiation. [ABSTRACT FROM AUTHOR]

Exercise induces signaling networks to improve muscle function and confer health benefits. To identify divergent and common signaling networks during and after different exercise modalities, we performed a phosphoproteomic analysis of human skeletal muscle from a cross-over intervention of endurance, sprint, and resistance exercise. This identified 5,486 phosphosites regulated during or after at least one type of exercise modality and only 420 core phosphosites common to all exercise. One of these core phosphosites was S67 on the uncharacterized protein C18ORF25, which we validated as an AMPK substrate. Mice lacking C18ORF25 have reduced skeletal muscle fiber size, exercise capacity, and muscle contractile function, and this was associated with reduced phosphorylation of contractile and Ca2+ handling proteins. Expression of C18ORF25 S66/67D phospho-mimetic reversed the decreased muscle force production. This work defines the divergent and canonical exercise phosphoproteome across different modalities and identifies C18ORF25 as a regulator of exercise signaling and muscle function. [Display omitted] • Comparative muscle phosphoproteome of endurance, sprint, and resistance exercise • Identification of the canonical muscle exercise phosphoproteome • Identification of C18ORF25 as an AMPK substrate • Phosphorylation of C18ORF25 regulates skeletal muscle contractile function Blazev et al. characterized the signaling pathways regulated during three different types of exercise in human skeletal muscle. They identified the uncharacterized protein C18ORF25 as a target of AMPK and a new regulator of exercise capacity and skeletal muscle function. [ABSTRACT FROM AUTHOR]

Summary The CRISPR/Cas9 technology enables the introduction of genomic alterations into almost any organism; however, systems for efficient and inducible gene modification have been lacking, especially for deletion of essential genes. Here, we describe a drug-inducible small guide RNA (sgRNA) vector system allowing for ubiquitous and efficient gene deletion in murine and human cells. This system mediates the efficient, temporally controlled deletion of MCL-1, both in vitro and in vivo, in human Burkitt lymphoma cell lines that require this anti-apoptotic BCL-2 protein for sustained survival and growth. Unexpectedly, repeated induction of the same sgRNA generated similar inactivating mutations in the human Mcl-1 gene due to low mutation variability exerted by the accompanying non-homologous end-joining (NHEJ) process. Finally, we were able to generate hematopoietic cell compartment-restricted Trp53 -knockout mice, leading to the identification of cancer-promoting mutants of this critical tumor suppressor. [ABSTRACT FROM AUTHOR]

Summary Apoptotic cell death removes unwanted cells and is regulated by interactions between pro-survival and pro-apoptotic members of the BCL-2 protein family. The regulation of apoptosis is thought to be crucial for normal embryonic development. Accordingly, complete loss of pro-survival MCL-1 or BCL-XL (BCL2L1) causes embryonic lethality. However, it is not known whether minor reductions in pro-survival proteins could cause developmental abnormalities. We explored the rate-limiting roles of MCL-1 and BCL-XL in development and show that combined loss of single alleles of Mcl-1 and Bcl-x causes neonatal lethality. Mcl-1 +/– ;Bcl-x +/– mice display craniofacial anomalies, but additional loss of a single allele of pro-apoptotic Bim (Bcl2l11) restores normal development. These findings demonstrate that the control of cell survival during embryogenesis is finely balanced and suggest that some human craniofacial defects, for which causes are currently unknown, may be due to subtle imbalances between pro-survival and pro-apoptotic BCL-2 family members. Graphical Abstract Highlights • Control of embryonic cell survival by BCL-2 family proteins is finely balanced • Combined loss of single alleles of Mcl-1 and Bcl-x causes craniofacial defects • Loss of one allele of Bim restores normal development to Mcl-1 +/− ;Bcl-x +/− pups Grabow et al. find that combined loss of single alleles of pro-survival Mcl-1 and Bcl-x causes craniofacial defects, including holoprosencephaly, a severe birth defect. Normal development is restored by concomitant loss of a single allele of pro-apoptotic Bim , revealing that cell survival and cell death during embryogenesis are finely balanced. [ABSTRACT FROM AUTHOR]

Summary Long-lived quiescent mammary stem cells (MaSCs) are presumed to coordinate the dramatic expansion of ductal epithelium that occurs through the different phases of postnatal development, but little is known about the molecular regulators that underpin their activation. We show that ablation of the transcription factor Foxp1 in the mammary gland profoundly impairs ductal morphogenesis, resulting in a rudimentary tree throughout life. Foxp1 -deficient glands were highly enriched for quiescent Tspan8hi MaSCs, which failed to become activated even in competitive transplantation assays, thus highlighting a cell-intrinsic defect. Foxp1 deletion also resulted in aberrant expression of basal genes in luminal cells, inferring a role in cell-fate decisions. Notably, Foxp1 was uncovered as a direct repressor of Tspan8 in basal cells, and deletion of Tspan8 rescued the defects in ductal morphogenesis elicited by Foxp1 loss. Thus, a single transcriptional regulator Foxp1 can control the exit of MaSCs from dormancy to orchestrate differentiation and development. Graphical Abstract Highlights • Foxp1 is an essential transcription factor for mammary gland development • Foxp1 controls the activation of quiescent MaSCs marked by Tspan8 • Foxp1 directly represses the transcription of Tspan8 in basal, but not luminal, cells • Tspan8 deletion rescues the Foxp1 -deficient mammary phenotype Fu et al. show that the transcriptional repressor Foxp1 is crucial for governing the exit of mammary stem cells from quiescence. Moreover, Tspan8 was identified as a direct Foxp1 target that plays a functional role in regulating the stem cell state, and its deletion reversed the effects of Foxp1 loss. [ABSTRACT FROM AUTHOR]