Multiscale 3D Genome Rewiring during Mouse Neural Development

Single-cell expression profiles of melanoma Tumors harbor multiple cell types that are thought to play a role in the development of resistance to drug treatments. Tirosh et al. used single-cell sequencing to investigate the distribution of these differing genetic profiles within melanomas. Many cells harbored heterogeneous genetic programs that reflected two different states of genetic expression, one of which was linked to resistance development. Following drug treatment, the resistance-linked expression state was found at a much higher level. Furthermore, the environment of the melanoma cells affected their gene expression programs. Science, this issue p. 189 Melanoma cells show transcriptional heterogeneity. To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.

Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.

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Integrative functional genomic analysis of human brain development and neuropsychiatric risks

Adr1p Carbon source-responsive zinc-finger transcription factor, required for transcription of the glucose-repressed gene ADH2, of peroxisomal protein genes, and of genes required for ethanol, glycerol, and fatty acid utilization (Direct: ChIP-on-chip) Cat8p derepression of a variety of genes under non-fermentative growth conditions, active after diauxic shift, binds carbon source responsive elements Hap4p Subunit of the heme-activated, glucose-repressed Hap2p/3p/4p/5p CCAAT-binding complex, a transcriptional activator and global regulator of respiratory gene expression; provides the principal activation function of the complex Indirect: Microarrays-Wild type vs. TF mutant) Stp1/Stp2 Homologous transcription factors, activated by proteolytic processing in response to signals from the SPS sensor system for external amino acids; activates transcription of amino acid permease genes and may have a role in tRNA processing

/pdf/jeonsainja-transcription-factor-wa-gigwanjiceonsig-17xfzho15k.pdf

전사인자(transcription factor)와 기관지천식

In 2003 Rubenstein and Merzenich hypothesized that some forms of Autism (ASD) might be caused by a reduction in signal-to-noise in key neural circuits, which could be the result of changes in excitatory-inhibitory (E-I) balance. Here, we have clarified the concept of E-I balance, and updated the original hypothesis in light of the field’s increasingly sophisticated understanding of neuronal circuits. We discuss how specific developmental mechanisms, which reduce inhibition, affect cortical and hippocampal functions. After describing how mutations of some ASD genes disrupt inhibition in mice, we close by suggesting that E-I balance represents an organizing framework for understanding findings related to pathophysiology and for identifying appropriate treatments.

Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders

Development and Functional Diversification of Cortical Interneurons

GABAergic interneurons (GABA, γ-aminobutyric acid) regulate neural-circuit activity in the mammalian cerebral cortex. These cortical interneurons are structurally and functionally diverse. Here, we use single-cell transcriptomics to study the origins of this diversity in the mouse. We identify distinct types of progenitor cells and newborn neurons in the ganglionic eminences, the embryonic proliferative regions that give rise to cortical interneurons. These embryonic precursors show temporally and spatially restricted transcriptional patterns that lead to different classes of interneurons in the adult cerebral cortex. Our findings suggest that shortly after the interneurons become postmitotic, their diversity is already patent in their diverse transcriptional programs, which subsequently guide further differentiation in the developing cortex.

Early emergence of cortical interneuron diversity in the mouse embryo

Understanding brain development remains a major challenge at the heart of understanding what makes us human The neocortex, in evolutionary terms the newest part of the cerebral cortex, is the seat of higher cognitive functions Its normal development requires the production, positioning and appropriate interconnection of very large numbers of both excitatory and inhibitory neurons Pax6 is one of a relatively small group of transcription factors that exert high-level control of cortical development, and whose mutation or deletion from developing embryos causes major brain defects and a wide range of neurodevelopmental disorders Pax6 is very highly conserved between primate and non-primate species, is expressed in a gradient throughout the developing cortex and is essential for normal corticogenesis Our understanding of Pax6’s functions and the cellular processes that it regulates during mammalian cortical development has significantly advanced in the last decade, owing to the combined application of genetic and biochemical analyses Here we review the functional importance of Pax6 in regulating cortical progenitor proliferation, neurogenesis, and formation of cortical layers and highlight important differences between rodents and primates We also review the pathological effects of PAX6 mutations in human neurodevelopmental disorders Finally, we discuss some aspects of Pax6’s molecular actions including its own complex transcriptional regulation, the distinct molecular functions of its splice variants and some of Pax6’s known direct targets which mediate its actions during cortical development

/pdf/regulation-of-cerebral-cortical-neurogenesis-by-the-pax6-569fltq302.pdf

Da Mi

Papers

Development and Functional Diversification of Cortical Interneurons

Early emergence of cortical interneuron diversity in the mouse embryo

Regulation of cerebral cortical neurogenesis by the Pax6 transcription factor

Pax6 Exerts Regional Control of Cortical Progenitor Proliferation via Direct Repression of Cdk6 and Hypophosphorylation of pRb

Cell-Autonomous Repression of Shh by Transcription Factor Pax6 Regulates Diencephalic Patterning by Controlling the Central Diencephalic Organizer