INO80 requires a polycomb subunit to regulate the establishment of poised chromatin in murine spermatocytes

ABSTRACT INO80 is the catalytic subunit of the INO80-chromatin remodeling complex that is involved in DNA replication, repair and transcription regulation. Ino80 deficiency in murine spermatocytes (Ino80cKO) results in pachytene arrest of spermatocytes due to incomplete synapsis and aberrant DNA double-strand break repair, which leads to apoptosis. RNA-seq on Ino80cKO spermatocytes revealed major changes in transcription, indicating that an aberrant transcription program arises upon INO80 depletion. In Ino80WT spermatocytes, genome-wide analysis showed that INO80-binding sites were mostly promoter proximal and necessary for the regulation of spermatogenic gene expression, primarily of premeiotic and meiotic genes. Furthermore, most of the genes poised for activity, as well as those genes that are active, shared INO80 binding. In Ino80cKO spermatocytes, most poised genes demonstrated de-repression due to reduced H3K27me3 enrichment and, in turn, showed increased expression levels. INO80 interacts with the core PRC2 complex member SUZ12 and promotes its recruitment. Furthermore, INO80 mediates H2A.Z incorporation at the poised promoters, which was reduced in Ino80cKO spermatocytes. Taken together, INO80 is emerging as a major regulator of the meiotic transcription program by mediating poised chromatin establishment through SUZ12 binding.

Frameshift Variant in ARID2 in a Chilean Individual with Coffin–Siris Syndrome Phenotype

Coffin–Siris syndrome (CSS) is one of the several causes of intellectual disability (ID) and, since its first description, has posed diagnostic challenges given its variability and phenotypic overlap with other alterations of chromatin-remodeling-associated syndromes. It is genetically heterogeneous, and causative mutations are detected in less than 70% of cases. The different subtypes of the syndrome described to date are caused by mutations in genes that encode subunits of the SWI/SNF chromatin-remodeling complex, which plays an essential role in the regulation of gene expression during embryogenesis. Whole exome sequencing (WES) has allowed the identification of pathogenic mutations in these genes, including ARID2. ARID2 is one of the primary components of the SWI/SNF complex and has been associated with ID and phenotypes similar to CSS for the first time in 2015. Fifteen published case reports have identified loss-of-function mutations, suggesting that the underlying pathogenic disease mechanism is haploinsufficiency of ARID2.We herein presented the case of an 8-year-old Chilean girl with clinical suspicion of CSS, in whom a novel frameshift variant in ARID2 was identified by WES. She was the first reported case in Latin America to our knowledge and her phenotype displays the main clinical features suggestive of CSS described in other patients with ARID2 variants. However, she did not present behavioral abnormalities, a characteristic frequently reported in the majority of patients with ARID2 variants, and also had some features, such as sparse scalp hair, which is frequently reported as a manifestation of CSS, but is uncommon in this new group of patients.

A Non-Canonical Function of Arabidopsis ERECTA Proteins in Gibberellin Signaling

The Arabidopsis ERECTA family (ERf) of leucine-rich repeat receptor-like kinases (LRR-RLKs), comprising ERECTA (ER), ERECTA-LIKE 1 (ERL1) and ERECTA-LIKE 2 (ERL2), control epidermal patterning, inflorescence architecture, stomata development, and hormonal signaling. Here we show that the er/erl1/erl2 triple mutant exhibits impaired gibberellin (GA) biosynthesis and perception alongside broad transcriptional changes. ERf proteins interact in the nucleus, via kinase domains, with the SWI3B subunit of the SWI/SNF chromatin remodeling complex (CRCs). The er/erl1/erl2 triple mutant exhibits reduced SWI3B protein level and affected nucleosomal chromatin structure. The ER kinase phosphorylates SWI3B in vitro, and the inactivation of all ERf proteins leads to the decreased phosphorylation of SWI3B protein in vivo. Correlation between DELLA overaccumulation and SWI3B proteasomal degradation together with the physical interaction of SWI3B with DELLA proteins explain the lack of RGA accumulation in the GA- and SWI3B-deficient erf mutant plants. Co-localization of ER and SWI3B on GID1 (GIBBERELLIN INSENSITIVE DWARF 1) DELLA target gene promoter regions and abolished SWI3B binding to GID1 promoters in er/erl1/erl2 plants supports the conclusion that ERf-SWI/SNF CRC interaction is important for transcriptional control of GA receptors. Thus, the involvement of ERf proteins in transcriptional control of gene expression, and observed similar features for human HER2 (Epidermal Growth Family Receptor-member), indicate an exciting target for further studies of evolutionarily conserved non-canonical functions of eukaryotic membrane receptors.ONE SENTENCE SUMMARYERECTA leucine-rich receptor-like kinase and SWI3B subunit of SWI/SNF chromatin remodeling complex cooperate in direct transcriptional control of GID1 genes in Arabidopsis.

SWI/SNF chromatin remodeling complex is required for initiation of sex-dependent differentiation in mouse germline

Sexual reproduction involves the creation of sex-dependent gametes, oocytes and sperm. In mammals, sexually dimorphic differentiation commences in the primordial germ cells (PGCs) in embryonic gonads; PGCs in ovaries and testes differentiate into meiotic primary oocytes and mitotically quiescent prospermatogonia, respectively. Here, we show that the transition from PGCs to sex-specific germ cells was abrogated in conditional knockout mice carrying a null mutation of Smarcb1 (also known as Snf5) gene, which encodes a core subunit of the SWI/SNF chromatin remodeling complex. In female mutant mice, failure to upregulate meiosis-related genes resulted in impaired meiotic entry and progression, including defects in synapsis formation and DNA double strand break repair. Mutant male mice exhibited delayed mitotic arrest and DNA hypomethylation in retrotransposons and imprinted genes, resulting from aberrant expression of genes related to growth and de novo DNA methylation. Collectively, our results demonstrate that the SWI/SNF complex is required for transcriptional reprogramming in the initiation of sex-dependent differentiation of germ cells.

Multiple functions of SWI/SNF chromatin remodeling complex in plant-pathogen interactions

The SWI/SNF chromatin remodeling complex utilizes the energy of ATP hydrolysis to facilitate chromatin access and plays essential roles in DNA-based events. Studies in animals, plants and fungi have uncovered sophisticated regulatory mechanisms of this complex that govern development and various stress responses. In this review, we summarize the composition of SWI/SNF complex in eukaryotes and discuss multiple functions of the SWI/SNF complex in regulating gene transcription, mRNA splicing, and DNA damage response. Our review further highlights the importance of SWI/SNF complex in regulating plant immunity responses and fungal pathogenesis. Finally, the potentials in exploiting chromatin remodeling for management of crop disease are presented.

Alterations of Chromatin Regulators in the Pathogenesis of Urinary Bladder Urothelial Carcinoma

Urothelial carcinoma (UC) is the most frequent histological type of cancer in the urinary bladder. Genomic changes in UC activate MAPK and PI3K/AKT signal transduction pathways, which increase cell proliferation and survival, interfere with cell cycle and checkpoint control, and prevent senescence. A more recently discovered additional category of genetic changes in UC affects chromatin regulators, including histone-modifying enzymes (KMT2C, KMT2D, KDM6A, EZH2), transcription cofactors (CREBBP, EP300), and components of the chromatin remodeling complex SWI/SNF (ARID1A, SMARCA4). It is not yet well understood how these changes contribute to the development and progression of UC. Therefore, we review here the emerging knowledge on genomic and gene expression alterations of chromatin regulators and their consequences for cell differentiation, cellular plasticity, and clonal expansion during UC pathogenesis. Our analysis identifies additional relevant chromatin regulators and suggests a model for urothelial carcinogenesis as a basis for further mechanistic studies and targeted therapy development.

An epigenetic circuit controls neurogenic programs during neocortex development

ABSTRACT The production and expansion of intermediate progenitors (IPs) are essential for neocortical neurogenesis during development and over evolution. Here, we have characterized an epigenetic circuit that precisely controls neurogenic programs, particularly properties of IPs, during neocortical development. The circuit comprises a long non-coding RNA (LncBAR) and the BAF (SWI/SNF) chromatin-remodeling complex, which transcriptionally maintains the expression of Zbtb20. LncBAR knockout neocortex contains more deep-layer but fewer upper-layer projection neurons. Intriguingly, loss of LncBAR promotes IP production, but paradoxically prolongs the duration of the cell cycle of IPs during mid-later neocortical neurogenesis. Moreover, in LncBAR knockout mice, depletion of the neural progenitor pool at embryonic stage results in fewer adult neural progenitor cells in the subventricular zone of lateral ventricles, leading to a failure in adult neurogenesis to replenish the olfactory bulb. LncBAR binds to BRG1, the core enzymatic component of the BAF chromatin-remodeling complex. LncBAR depletion enhances association of BRG1 with the genomic locus of, and suppresses the expression of, Zbtb20, a transcription factor gene known to regulate both embryonic and adult neurogenesis. ZBTB20 overexpression in LncBAR-knockout neural precursors reverses compromised cell cycle progressions of IPs.

Phenotypic and molecular spectra of patients with switch/sucrose nonfermenting complex-related intellectual disability disorders in Korea

Background The switch/sucrose nonfermenting (SWI/SNF) complex is an adenosine triphosphate-dependent chromatin-remodeling complex associated with the regulation of DNA accessibility. Germline mutations in the components of the SWI/SNF complex are related to human developmental disorders, including the Coffin–Siris syndrome (CSS), Nicolaides–Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. These disorders are collectively referred to as SWI/SNF complex-related intellectual disability disorders (SSRIDDs). Methods Whole-exome sequencing was performed in 564 Korean patients with neurodevelopmental disorders. Twelve patients with SSRIDDs (2.1%) were identified and their medical records were retrospectively analyzed. Results ARID1B, found in eight patients, was the most frequently altered gene. Four patients harbored pathogenic variants in SMARCA4, SMARCB1, ARID2, and SMARCA2. Ten patients were diagnosed with CSS, and one patient without a typical phenotype was diagnosed with ARID1B-related nonsyndromic intellectual disability. Another patient harboring the SMARCA2 pathogenic variant was diagnosed with NCBRS. All pathogenic variants in ARID1B were truncating, whereas variants in SMARCA2, SMARCB1, and SMARCA4 were nontruncating (missense). Frequently observed phenotypes were thick eyebrows (10/12), hypertrichosis (8/12), coarse face (8/12), thick lips (8/12), and long eyelashes (8/12). Developmental delay was observed in all patients, and profound speech delay was also characteristic. Agenesis or hypoplasia of the corpus callosum was observed in half of the patients (6/12). Conclusions SSRIDDs have a broad disease spectrum, including NCBRS, CSS, and ARID1B-related nonsyndromic intellectual disability. Thus, SSRIDDs should be considered as a small but important cause of human developmental disorders.