Compartmentalized regulation of RNAs is emerging as a key driver of developmental transitions, with RNA-binding proteins performing specialized functions in different subcellular compartments. The RNA-binding protein Mei2, which arrests mitotic proliferation and drives zygotic development in fission yeast, was shown to function in the nucleus to trigger meiotic divisions. Here, using compartment-restricted

The production of B cells is essential for a functional immune system. This process relies on the coordinated activity of a handful of transcription factors that act in part by modifying the chromatin landscape of lymphoid progenitors to allow the ordered expression of genes essential for B-cell development. In this issue of Genes & Development, Tingvall-Gustafsson and colleagues (doi:10.1101/gad.353002

One of the densest compartments in the cell is the dense fibrillar component (DFC) of the nucleolus, consisting mainly of nascent ribosomal RNA (rRNA), small nucleolar ribonucleoproteins (snoRNPs), and their chaperone, Nopp140 (gene name NOLC1). How this biomolecular condensate is formed and what underlies its structure and function are poorly understood, like those of most liquid–liquid phase-separated

During neurodevelopment, a single progenitor cell can generate many different neuron types. As these neurons mature, they form unique morphologies, integrate into neural circuits, and contribute to behavior. However, the integration of these developmental events is understudied. Here, we show that the same transcription factor is important for both the generation of neuronal diversity and maintaining

The Eyes Absent family of protein phosphatases (EYA1–4) is aberrantly expressed and tumor-promoting across many devastating cancers of neurological origin affecting both children and adults. It has recently been demonstrated that EYA1 and EYA4 promote tumor cell survival by increasing the active pool of Polo-like kinase 1 (PLK1) molecules. This discovery provides a rationale for the therapeutic combination

To increase our understanding of the interplay between transcription factor networks and the epigenetic landscape in early B-lymphoid development, we conducted combined SC-RNA/ATAC-seq analyses of bone marrow progenitor populations. Based on changes in DNA accessibility, we created a high-resolution model for B-cell development. Trend change analysis identified a rapid shift in DNA accessibility, resulting

John Gurdon was a curiosity-based inquisitor of embryonic development, beguiled by its mysteries, and he stayed with this focus all his career. His landmark cloning of Xenopus laevis using a donor nucleus from adult somatic tissue conclusively settled a longstanding question and was foundational to cloning of a mammal and subsequent advances in nuclear reprogramming. He was awarded the 2012 Nobel Prize

Precise control of microRNA (miRNA) expression is critical during development. An important mechanism of miRNA regulation is target-directed microRNA degradation (TDMD), a pathway in which the binding of miRNAs to specialized trigger RNAs induces ubiquitylation and decay of associated argonaute (AGO) proteins by the ZSWIM8 ubiquitin ligase. Concomitant release of miRNAs results in their rapid turnover

Pioneer transcription factors (TFs) such as SOX2 play critical roles in the control of stem cell identity and are dysregulated in many human cancers. For example, SOX2 regulates the self-renewal of neural stem cells (NSCs) and is typically highly expressed in glioblastoma stem cells (GSCs), where it is known to induce an immature NSC-like state. Here, we explored the regulation of SOX2 by phosphorylation

High-grade serous ovarian cancer (HGSOC) is a highly lethal gynecologic malignancy in women. Women diagnosed with HGSOC initially respond to chemotherapy, but there is a >80% rate of relapse. There is thus a significant unmet need for new therapeutic targets for HGSOC. Estrogen receptor α (ERα) is a particularly attractive candidate, as ∼70% of HGSOC tumors stain positively for ERα and there are approved

Genes & Development 27: 2576–2589 (2013)

Poly(A) tails of newly synthesized mRNAs have uniform lengths, arising through cooperation between the cleavage and polyadenylation complex (CPAC) and poly(A) binding proteins (PABPs). In the budding yeast Saccharomyces cerevisiae, the responsible PABP is the evolutionarily conserved CCCH zinc finger protein Nab2 that facilitates the biogenesis of ∼60 adenosine mRNA poly(A) tails. Here, we address

Heterozygous missense mutations in EZH2 cause Weaver syndrome (WS), a developmental disorder characterized by intellectual disability and overgrowth. EZH2 encodes the enzymatic subunit of Polycomb repressive complex 2 (PRC2), which mediates monomethylation, dimethylation, and trimethylation of histone H3 lysine 27 (H3K27me1/2/3). Most WS-associated EZH2 variants lack functional characterization but

Cortical radial glia (RGs) sequentially generate pyramidal neurons (PyNs) and glia. In this study, we investigated the cell-intrinsic programs underlying cortical cellular diversification using time-series scRNA-seq and snATAC-seq on purified mouse cortical progenitors across embryonic and postnatal stages. Our data revealed that RGs transition from early to late over time, sequentially producing intermediate

Regulators of chromatin accessibility play key roles in cell fate transitions, triggering the onset of novel transcription programs as cells differentiate. In the Drosophila male germline stem cell lineage, tMAC, a master regulator of spermatocyte differentiation that binds thousands of loci, is required for local opening of chromatin, allowing activation of spermatocyte-specific promoters. Here we

We report here on the identification of a previously unrecognized property of MYOD as a repressor of gene expression via E-box-independent chromatin binding during the process of somatic cell trans-differentiation into skeletal muscle. When ectopically expressed in proliferating human fibroblasts or endogenously induced in activated muscle stem cells (MuSCs), MYOD was detected at accessible regulatory

Mammalian genomes undergo pervasive transcription in both genic and intergenic regions. Trimethylation of histone H3 lysine 4 (H3K4me3) is a deeply conserved and functionally important histone modification enriched at transcriptionally active promoters, where it facilitates RNA polymerase activity. H3K4me3 is also commonly found in intergenic regions, where its role is poorly understood. We interrogated

Vitamin B6 is a metabolic cofactor that underpins critical regulatory pathways, including amino acid flux, one-carbon pathways, redox homeostasis, and neurotransmitter biosynthesis. Emerging evidence suggests that vitamin B6 deficiency or its metabolic dysregulation perturbs these core metabolic pathways, driving oncogenic programs in both solid tumors and hematologic malignancies. Moreover, vitamin

MyoD is well known for its ability to reprogram a broad range of cell types into myogenic cells and for its pioneer function in activating the myogenic program during muscle development and regeneration. The basic helix–loop–helix (bHLH) protein achieves this by directly binding to E-boxes in DNA and recruiting proteins like histone acetyltransferases and the SWI/SNF chromatin remodeling complex. Interestingly

Polyadenylation of mRNA is a key step in post-transcriptional regulation. In this issue of Genes & Development, Gabs and colleagues (doi:10.1101/gad.352912.125) provide evidence for a novel, kinetically driven mechanism that dictates the length of poly(A) tails added to mRNAs in budding yeast. The investigators introduce the concept of Nab2, a zinc finger poly(A) RNA binding protein, as a “kinetic

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC). The molecular mechanisms underlying the progression of CRPC toward NEPC remain incompletely understood, and effective treatments remain to be discovered. Here, we report that loss of the nuclear receptor ERRγ promotes neuroendocrine differentiation in a Pten-deficient mouse model of prostate adenocarcinoma

Precise intercellular communication is critical for cellular decision-making. The segmentation clock is an oscillatory gene network regulating periodic segmentation of the presomitic mesoderm (PSM) in vertebrate embryos. Oscillations between neighboring cells are thought to be coupled by DELTA–NOTCH signaling. To directly test this experimentally, Isomura and colleagues (doi:10.1101/gad.352538.124)

Mitochondria play a crucial role in cellular energy metabolism and homeostasis and are strongly implicated in aging and age-related diseases. The outer mitochondrial membrane protein voltage-dependent anion channel (VDAC) plays multiple roles in mitochondrial homeostasis, including transport of metabolites, ATP, and Ca2+. Dysregulation of VDAC levels has been associated with cancer, neurodegeneration

During vertebrate development, the segmentation clock drives oscillatory gene expression in the presomitic mesoderm (PSM), leading to the periodic formation of somites. Oscillatory gene expression is synchronized at the cell population level; inhibition of Delta–Notch signaling results in the loss of synchrony and the fusion of somites. However, it remains unclear how cell–cell signaling couples oscillatory

The mechanisms governing the generation of neuronal subtypes at distinct times and proportions during human retinal development are poorly understood. While thyroid hormone (TH) signaling specifies cone photoreceptor subtypes, how this regulation changes over time remains unclear. To address this question, we studied the expression and function of type 3 iodothyronine deiodinase (DIO3), an enzyme that

The exon junction complex (EJC) has roles in mRNA export and cytoplasmic quality control. However, the EJC is recruited to pre-mRNA by the spliceosome prior to the completion of splicing. When splicing is cotranscriptional, the EJC is deposited on nascent RNA early during synthesis, raising the question of whether the EJC regulates downstream RNA processing. Here we show, using long-read sequencing

Polycomb chromatin domains are chromosomal regions decorated with histone H2A monoubiquitination at lysine 119 (H2Aub1) and histone H3 trimethylation at lysine 27 (H3K27me3). These domains are dynamically shaped through the actions of different Polycomb group protein complexes to control gene expression during development. To assess how different Polycomb group subcomplexes contribute to these histone

Stabilization of β-catenin on the dorsal side of the embryo is critical for the formation of the dorsal organizer. The novel transmembrane protein Huluwa (Hwa) has recently been identified as the maternal dorsal determinant responsible for β-catenin stabilization in dorsal organizer formation. The molecular mechanism by which Hwa induces WNT-independent β-catenin stabilization remains elusive. In this

Genes & Development 31: 1243–1256 (2017)

In response to excess nutrients, white adipose tissue expands by both generating new adipocytes and upregulating lipogenesis in existing adipocytes. Here, we performed a genome-wide functional CRISPR screen to identify regulators of adipogenesis in the mouse 3T3-L1 preadipocyte model. In this pooled screening strategy, we used FACS to isolate populations based on lipid content, gating for fluorescence

Myeloid leukemias are heterogeneous cancers with diverse mutations, sometimes in genes with unclear roles and unknown functional partners. PHF6 and PHIP are two poorly understood chromatin-binding proteins recurrently mutated in acute myeloid leukemia (AML). PHF6 mutations are associated with poorer outcomes, whereas PHIP was recently identified as the most common selective mutation in Black patients

MicroRNAs (miRNAs) are short RNAs that post-transcriptionally regulate gene expression. In canonical miRNA biogenesis, primary miRNAs are transcribed from intergenic loci or intronic regions by RNA polymerase II and sequentially cleaved by the Microprocessor complex and Dicer, and the resulting mature miRNAs are loaded into Argonaute to repress target mRNAs. A minority of miRNAs are generated via noncanonical

Histone mRNAs are the only nonpolyadenylated mRNAs in eukaryotic cells and require specialized processing in the histone locus body (HLB), a nuclear body where essential processing factors, including the U7 snRNP, are concentrated. Recent studies have revealed that misregulation of histone pre-mRNA processing can lead to polyadenylation of histone mRNAs and disruption of histone protein homeostasis

Oligoadenylate synthetases (OASs) are ancient proteins that play a critical role in combatting viruses in mammals. OASs are known to antagonize viral replication by binding viral dsRNA and synthesizing 2′–5′-oligo(A), which activates the antiviral endoribonuclease RNase L. Here, we investigate the antiviral activities of the human OAS isoforms (OAS1, OAS2, OAS3, and OASL) during West Nile virus (WNV)

The tardigrade damage suppressor (Dsup) and vertebrate high-mobility group N (HMGN) proteins bind specifically to nucleosomes via a conserved motif whose structure has not been experimentally determined. Here we used cryo-EM to show that both proteins bind to the nucleosome acidic patch via analogous arginine anchors with one molecule bound to each face of the nucleosome. We additionally used the natural

Throughout the last century, aneuploidy has been cemented as a hallmark of cancer. Although the association of aneuploidy with tumorigenesis has been well established, the role of these genetic imbalances in tumor formation has only recently begun to be elucidated. Advancements in genomics have revealed the complexity and context dependence of the effect of aneuploidy on cancer growth, while developments

Growing disparities in treatment outcomes for acute myeloid leukemia (AML) call for particular attention to features of the disease that vary among populations. In this issue of Genes & Development, Pawar and colleagues (doi:10.1101/gad.352602.125) now reveal that mutations in PHIP, more prevalent among Black patients with AML, disrupt the function of the chromatin regulator PHF6. They corroborate

Precise control of miRNA biogenesis is of extreme importance, because misregulation of miRNAs underlies or exacerbates many disease states. The Microprocessor complex, composed of DROSHA and DGCR8, carries out the first cleavage step in canonical miRNA biogenesis. Despite recent advances in understanding the molecular mechanism of Microprocessor, the N-terminal region of DROSHA is less characterized

Heart formation depends on the finely tuned activity of transcriptional regulators, yet the networks they control are only now being defined. In this issue of Genes & Development, Muncie-Vasik and colleagues (doi:10.1101/gad.352889.125) analyzed the role of MEF2C, which is a key driver of heart formation. By characterizing MEF2C's temporal effects on mRNA profiles and chromatin structure, the investigators

Transcription of protein-coding genes by RNA polymerase II involves a characteristic pausing event downstream from transcription start sites. Such promoter-proximal pausing likely represents a transcription checkpoint, which ensures proper assembly of a fully functional RNAPII elongation complex that is capable of transcribing through the chromatin environment, with correctly modified nascent pre-mRNA

Pulmonary fibrosis is a lethal disease associated with damaging insults to the lung and with organismal aging. The presence of short and dysfunctional telomeres has been placed at the origin of this disease in a percentage of both familial and sporadic cases. Recently, a mutation in the telomere-binding protein protection of telomeres 1 in humans (hPOT1), the hPOT1 L259S mutation, was found in families

Enhancer RNAs (eRNAs) are transcribed by RNA polymerase IIduring enhancer activation but are typically rapidly degraded in the nucleus. During states of reduced RNA surveillance, however, eRNAs and other similar “noncoding” RNAs (including, e.g., upstream antisense RNAs) are stabilized, and some are exported to the cytoplasm and can even be found on polysomes. Here, we report unexpectedly that ∼12%

Adipose tissue is rapidly expanding early in life. Elucidating the queues facilitating this process will advance our understanding of metabolically healthy obesity. Using single-cell RNA sequencing, we identified compositional differences of prewean and adult murine subcutaneous adipose tissue. We identified a dipeptidyl peptidase-4 (Dpp4)-positive precursor population residing in the reticular interstitium

For neurons to establish the correct connections in animal nervous systems, interactions between cell adhesion molecules (CAMs), expressed presynaptically and postsynaptically, are thought to guide neurons to their targets. Here, we assess the role that affinity between two cognate CAMs—DIP-α and Dpr10—plays in establishing the leg neuromuscular system in Drosophila. If affinity decreases or, surprisingly

Genes & Development 32: 1525–1536 (2018)

Genes & Development 37: 303–320 (2023)

Malaria-transmitting mosquitoes are extremely sexually dimorphic in their anatomy and behavior. Sex-specific gene expression in Anopheles gambiae is well studied in adult stages, but its onset during embryogenesis, apart from sex determination factors like Yob, remains largely unknown. Here, we report a comprehensive single-embryo transcriptome atlas of A. gambiae males and females to understand the

Lineage plasticity is critical for tumor progression and therapy resistance, but the molecular mechanisms underlying cell identity shifts in cancer remain poorly understood. In lung adenocarcinoma (LUAD), the loss of pulmonary lineage fidelity and acquisition of alternate identity programs converge on hybrid identity (hybrid ID) states, which are postulated to be key intermediates in LUAD evolution

Circular RNAs (circRNAs) arise from back-splicing of precursor RNAs and accumulate in the nervous systems of animals, where they are thought to regulate gene expression and synaptic function. Here, we show that neuronal circRNA biosynthesis is mediated by the pan-neuronal RNA-binding protein ELAV. In Drosophila embryos, we characterized the circRNA landscape in normal and elav mutant neurons. We found

The Hippo pathway regulates many physiological processes, including development, tumor suppression, and wound healing. One understudied Hippo pathway component is PTPN14, an evolutionarily conserved tyrosine phosphatase that inhibits YAP/TAZ. Although it is an established tumor suppressor, PTPN14's role in tissue homeostasis has remained unclear. We thus generated Ptpn14-deficient mice and found that

The segmentation clock is a molecular oscillator that regulates the timing of somite formation in the developing vertebrate embryo. NOTCH signaling is one of the key pathways required for proper functioning of the segmentation clock. Aberrant NOTCH signaling results in developmental abnormalities such as congenital scoliosis as well as diseases such as T-cell acute lymphoblastic lymphoma (T-ALL). In

Mammalian enhancers can regulate genes over large genomic distances, often skipping over other genes. Despite this, precise developmental regulation suggests that mechanisms exist to ensure enhancers only activate their correct targets. Sculpting of three-dimensional chromosome organization through cohesin-dependent loop extrusion is thought to be important for facilitating and constraining enhancer

Differential mRNA expression is essential for driving cell type identity and cell fate transitions during tissue differentiation and organismal development. However, transcription kinetics are seemingly heterogeneous at a cell-to-cell level, occurring in a series of episodic bursts of nascent mRNA synthesis separated by refractory periods. This transcriptional bursting therefore affects both the speed

Lineage plasticity drives treatment resistance in lung adenocarcinoma (LUAD) as cancer cells adopt new identities. In this issue of Genes & Development, Fort and colleagues (doi:10.1101/gad.352742.125) report HNF4α as a key regulator of hybrid identity states and tumor progression in NKX2-1-positive LUAD. Using murine and human models, they show that HNF4α promotes gastrointestinal/liver-like programs

Although vertebrates share a similar body plan, different vertebrate species can develop at very different rates. In recent years, there has been an increasing appreciation of the fact that protein stability regulates the pace of differentiation. For example, global differences in protein stability may help explain why humans develop more slowly than mice. Mechanisms controlling the stability of particular

The gene regulatory networks (GRNs) that control early heart formation are beginning to be understood, but lineage-specific GRNs remain largely undefined. We investigated networks controlled by the vital transcription factor MEF2C using a time course of single-nucleus RNA sequencing and ATAC sequencing in wild-type and Mef2c-null embryos. We identified a “posteriorized” cardiac gene signature and chromatin

The unfolded protein response (UPR) was discovered in budding yeast as a mechanism that allows cells to adapt to endoplasmic reticulum (ER) stressors. Although the UPR is not thought to be necessary for cellular fitness of wild-type cells in the absence of stress, we found that UPR deficiency led to poor growth in cycling mitotic yeast cells. This led to pervasive adaptive aneuploidy of specific chromosomes

Ovarian aging is a critical yet understudied driver of systemic aging in female bodies, with profound implications for female health and longevity. Despite its significance, we still know little about ovarian aging and its systemic effects on aging trajectories. With new efforts over the past few years, interest in the field has been growing and there is momentum to address these questions. This review

The rising global demographic aging and the subsequent increase in the prevalence of age-related diseases highlight the need to understand aging biology. A key player in organismal aging is the immune system, which has broad systemic effects. On the one hand, immune aging involves the decline of hematopoietic stem cells and significant alterations in the functionality and composition of both innate

Excessive levels of oncogenic RAS expression in normal cells trigger reactive cellular senescence, known as oncogene-induced senescence (OIS)—a putative autonomous tumor-suppressive mechanism. However, the monoallelic expression of oncogenic RAS from the endogenous locus often fails to induce senescence, at least in the short term. Consequently, whether robust senescence characterizes the preneoplasia