Calcium-permeable AMPA receptors govern PV neuron feature selectivity.

The brain helps us survive by forming internal representations of the external world1,2. Excitatory cortical neurons are often precisely tuned to specific external stimuli3,4. However, inhibitory neurons, such as parvalbumin-positive (PV) interneurons, are generally less selective5. PV interneurons differ from excitatory neurons in their neurotransmitter receptor subtypes, including AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs)6,7. Excitatory neurons express calcium-impermeable AMPARs that contain the GluA2 subunit (encoded by GRIA2), whereas PV interneurons express receptors that lack the GluA2 subunit and are calcium-permeable (CP-AMPARs). Here we demonstrate a causal relationship between CP-AMPAR expression and the low feature selectivity of PV interneurons. We find low expression stoichiometry of GRIA2 mRNA relative to other subunits in PV interneurons that is conserved across ferrets, rodents, marmosets and humans, and causes abundant CP-AMPAR expression. Replacing CP-AMPARs in PV interneurons with calcium-impermeable AMPARs increased their orientation selectivity in the visual cortex. Manipulations to induce sparse CP-AMPAR expression demonstrated that this increase was cell-autonomous and could occur with changes beyond development. Notably, excitatory-PV interneuron connectivity rates and unitary synaptic strength were unaltered by CP-AMPAR removal, which suggested that the selectivity of PV interneurons can be altered without markedly changing connectivity. In Gria2-knockout mice, in which all AMPARs are calcium-permeable, excitatory neurons showed significantly degraded orientation selectivity, which suggested that CP-AMPARs are sufficient to drive lower selectivity regardless of cell type. Moreover, hippocampal PV interneurons, which usually exhibit low spatial tuning, became more spatially selective after removing CP-AMPARs, which indicated that CP-AMPARs suppress the feature selectivity of PV interneurons independent of modality. These results reveal a new role of CP-AMPARs in maintaining low-selectivity sensory representation in PV interneurons and implicate a conserved molecular mechanism that distinguishes this cell type in the neocortex.

A Zinc Finger Transcription Factor Faithfully Dedicated to Only a Single Target Gene in Erythroid Cells.

Lan et al. carry out a CRISPR-mediated genetic screen and discover that ZNF410 uniquely regulates the NuRD component CHD4 to repress γ-globin transcription in erythroid cells, establishing a novel fetal hemoglobin regulatory mechanism.

Arabidopsis HEAT SHOCK FACTOR BINDING PROTEIN is required to limit meiotic crossovers and HEI10 transcription.

The number of meiotic crossovers is tightly controlled and most depend on pro-crossover ZMM proteins, such as the E3 ligase HEI10. Despite the importance of HEI10 dosage for crossover formation, how HEI10 transcription is controlled remains unexplored. In a forward genetic screen using a fluorescent crossover reporter in Arabidopsis thaliana, we identify heat shock factor binding protein (HSBP) as a repressor of HEI10 transcription and crossover numbers. Using genome-wide crossover mapping and cytogenetics, we show that hsbp mutations or meiotic HSBP knockdowns increase ZMM-dependent crossovers toward the telomeres, mirroring the effects of HEI10 overexpression. Through RNA sequencing, DNA methylome, and chromatin immunoprecipitation analysis, we reveal that HSBP is required to repress HEI10 transcription by binding with heat shock factors (HSFs) at the HEI10 promoter and maintaining DNA methylation over the HEI10 5' untranslated region. Our findings provide insights into how the temperature response regulator HSBP restricts meiotic HEI10 transcription and crossover number by attenuating HSF activity.

Long noncoding RNA GATA2AS influences human erythropoiesis by transcription factor and chromatin landscape modulation.

ABSTRACT: Long noncoding RNAs (lncRNAs) are extensively expressed in eukaryotic cells and have been revealed to be important for regulating cell differentiation. Many lncRNAs have been found to regulate erythroid differentiation in the mouse. However, given the low sequence conservation of lncRNAs between mouse and human, our understanding of lncRNAs in human erythroid differentiation remains incomplete. lncRNAs are often transcribed opposite to protein coding genes and regulate their expression. Here, we characterized a human erythrocyte-expressed lncRNA, GATA2AS, which is transcribed opposite to erythroid transcription regulator GATA2. GATA2AS is a 2080-bp long, primarily nucleus-localized noncoding RNA that is expressed in erythroid progenitor cells and decreases during differentiation. Knockout of GATA2AS in human HUDEP2 erythroid progenitor cells using CRISPR-Cas9 genome editing to remove the transcription start site accelerated erythroid differentiation and dysregulated erythroblast gene expression. We identified GATA2AS as a novel GATA2 and HBG activator. Chromatin isolation by RNA purification showed that GATA2AS binds to thousands of genomic sites and colocalizes at a subset of sites with erythroid transcription factors including LRF and KLF1. RNA pulldown and RNA immunoprecipitation confirmed interaction between GATA2AS and LRF and KLF1. Chromatin immunoprecipitation sequencing (ChIP-seq) showed that knockout of GATA2AS reduces binding of these transcription factors genome wide. Assay for transposase-accessible chromatin sequencing (ATAC-seq) and H3K27ac ChIP-seq showed that GATA2AS is essential to maintain the chromatin regulatory landscape during erythroid differentiation. Knockdown of GATA2AS in human primary CD34+ cells mimicked results in HUDEP2 cells. Overall, our results implicate human-specific lncRNA GATA2AS as a regulator of erythroid differentiation by influencing erythroid transcription factor binding and the chromatin regulatory landscape.

Improvement in Facial Wrinkles Using Materials Enhancing PPARGC1B Expression Related to Mitochondrial Function.

Skin aging is an unavoidable natural phenomenon caused by intrinsic and extrinsic factors. In modern society, the pursuit of a wrinkle-free and aesthetically appealing face has gained considerable prominence. Numerous studies have aimed at mitigating the appearance of facial wrinkles. Antiaging research focused on regulating the function of mitochondria, the main reactive oxygen species-generating organelles, has been extensively conducted. In this study, we investigated the correlation between facial wrinkles and the expression of PPARGC1B, considering the association of this gene with mitochondrial function, to identify its potential as a target for exploring antiaging cosmetic materials. We elucidated the role of PPARGC1B in the skin and identified five bioactive materials that modulated its expression. The effectiveness of these materials was verified through in vitro experiments on human dermal fibroblasts. We prepared cosmetic formulations incorporating the five materials and confirmed their ability to enhance dermal collagen in three-dimensional skin models and reduce facial wrinkles under the eyes and nasolabial fold areas in human subjects. The study findings have significant implications for developing novel antiaging cosmetic formulations by reinforcing mitochondrial functions.

Efficacy of SGPP2 Modulation-Mediated Materials in Ameliorating Facial Wrinkles and Pore Sagging.

Skin aging is a complex process with internal and external factors. Recent studies have suggested that enlargement and elongation of skin pores may be early signs of aging in addition to wrinkles and loss of elasticity. This study explores the potential of targeting the SGPP2 gene in keratinocytes to address these emerging concerns. Using siRNA knockdown, we demonstrated that SGPP2 modulates the production of inflammatory cytokines (interleukin (IL)-1ß and IL-8). Furthermore, conditioned media experiments revealed that keratinocytes with high SGPP2 expression indirectly influence fibroblast extracellular matrix remodeling, potentially contributing to enlarged pores and wrinkle formation. Based on these findings, we explored a complex formulation containing four SGPP2-modulating compounds. In vitro and in vivo experiments demonstrated the efficacy of the formulation in mitigating fine wrinkles and pore enlargement. This study highlights the significant implications of developing a more effective antiaging cosmetic formulation by targeting underlying inflammatory processes that drive skin aging.

Hemogen/BRG1 cooperativity modulates promoter and enhancer activation during erythropoiesis.

Hemogen is a hematopoietic tissue-specific gene that regulates the proliferation and differentiation of hematopoietic cells; however, the mechanism underlying its function in erythropoiesis is unknown. We found that depletion of hemogen in human CD34+ erythroid progenitor cells and HUDEP2 cells significantly reduced the expression of genes associated with heme and hemoglobin synthesis, supporting a positive role for hemogen in erythroid maturation. In human K562 cells, hemogen antagonized the occupancy of corepressors nucleosome remodeling and histone deacetylase (NuRD) complex and facilitated LDB1 complex-mediated chromatin looping. Hemogen recruited SWI/SNF complex ATPase BRG1 as a coactivator to regulate nucleosome accessibility and H3K27ac enrichment for promoter and enhancer activity. To determine whether hemogen/BRG1 cooperativity is conserved in mammalian systems, we generated hemogen-knockout/knockin mice and investigated hemogen/BRG1 function in murine erythropoiesis. Loss of hemogen in embryonic days 12.5 to 16.5 fetal liver cells impeded erythroid differentiation through reducing the production of mature erythroblasts. Chromatin immunoprecipitation sequencing in wild-type and hemogen-knockout animals revealed that BRG1 is largely dependent on hemogen to regulate chromatin accessibility at erythroid gene promoters and enhancers. In summary, the hemogen/BRG1 interaction in mammals is essential for fetal erythroid maturation and hemoglobin production through its active role in promoter and enhancer activity and chromatin organization.

Complete genome sequences of two tombusvirus-like viruses identified in Echinacea purpurea seeds.

Echinacea is an herbaceous plant originating from North America that is cultivated for gardening and landscaping because of its showy flowers. Using high-throughput sequencing, we identified two viral contigs from echinacea seeds that were related to the family Tombusviridae. These two viruses were similar to oat chlorotic stunt virus (OCSV) and other unassigned tombusviruses; therefore, we tentatively named them Echinacea-associated tombusviruses 1 and 2 (EaTV1 and EaTV2, respectively). The EaTVs represent putative readthrough sites and have no poly(A) tails, aligning with the common features of family Tombusviridae. The EaTVs are included in a monophyletic group of OCSV and several unassigned tombusviruses. Because OCSV is the only member of Avenavirus to date, EaTVs are tentative members of Avenavirus, or they are close sister species to OCSV with several unassigned tombusviruses. RNA-dependent RNA polymerases and coat proteins were well conserved among EaTVs and unassigned tombusviruses; however, their similarities were not correlated, implying divergent and complex evolution.