scholarly journals Neuronal identity is maintained in the adult brain through KAT3-dependent enhancer acetylation

2019 ◽  
Author(s):  
Michal Lipinski ◽  
Rafael Muñoz-Viana ◽  
Beatriz del Blanco ◽  
Juan Medrano-Relinque ◽  
Angel Marquez-Galera ◽  
...  
Keyword(s):  
Cell Types ◽  
Adult Brain ◽  
Differentiated Cells ◽  
Excitatory Neurons ◽  
Neurological Phenotype ◽  
Neuronal Genes ◽  
Cell Type Specific ◽  
Chromatin Acetylation ◽  
Type 3 ◽  
Dendritic Complexity

ABSTRACTVery little is known about the mechanisms responsible for maintaining cell identity in mature tissues. The paralogous type 3 lysine acetyltransferases (KAT3) CBP and p300 are both essential during development, but their specific functions in nondividing differentiated cells remains unclear. Here, we show that when both proteins are simultaneously knocked-out in excitatory neurons of the adult brain, the mice express a rapidly progressing neurological phenotype associated with reduced dendritic complexity and electrical activity, the transcriptional shutdown of neuronal genes, and a dramatic loss of H3K27 acetylation and pro-neural transcription factor binding at neuronal enhancers. The neurons lacking both KAT3 rapidly acquire a molecularly undefined fate with no sign of dedifferentiation, transdifferentiation or death. Restoring CBP expression or lysine acetylation reestablished neuronal-specific transcription. Our experiments demonstrate that KAT3 proteins act as fate-keepers in excitatory neurons and other cell types by jointly safeguarding chromatin acetylation levels at cell type-specific enhancers throughout life.

scholarly journals Stem-cell-ubiquitous genes spatiotemporally coordinate division through regulation of stem-cell-specific gene networks

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Natalie M. Clark ◽  
Eli Buckner ◽  
Adam P. Fisher ◽  
Emily C. Nelson ◽  
Thomas T. Nguyen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Gene Networks ◽  
Cell Types ◽  
Specific Gene ◽  
Cell Renewal ◽  
Cell Type ◽  
Stem Cell Maintenance ◽  
Differentiated Cells ◽  
Cell Type Specific ◽  
Stem Cell Type

AbstractStem cells are responsible for generating all of the differentiated cells, tissues, and organs in a multicellular organism and, thus, play a crucial role in cell renewal, regeneration, and organization. A number of stem cell type-specific genes have a known role in stem cell maintenance, identity, and/or division. Yet, how genes expressed across different stem cell types, referred to here as stem-cell-ubiquitous genes, contribute to stem cell regulation is less understood. Here, we find that, in the Arabidopsis root, a stem-cell-ubiquitous gene, TESMIN-LIKE CXC2 (TCX2), controls stem cell division by regulating stem cell-type specific networks. Development of a mathematical model of TCX2 expression allows us to show that TCX2 orchestrates the coordinated division of different stem cell types. Our results highlight that genes expressed across different stem cell types ensure cross-communication among cells, allowing them to divide and develop harmonically together.

scholarly journals Neocortical layer 4 in adult mouse differs in major cell types and circuit organization between primary sensory areas

2018 ◽  
Author(s):  
F. Scala ◽  
D. Kobak ◽  
S. Shan ◽  
Y. Bernaerts ◽  
S. Laturnus ◽  
...  
Keyword(s):  
Adult Mouse ◽  
Building Blocks ◽  
Cell Types ◽  
Excitatory Input ◽  
Excitatory Neurons ◽  
Layer 4 ◽  
Cell Type Specific ◽  
Fast Spiking ◽  
Mouse Visual Cortex ◽  
Whole Cell Recordings

AbstractLayer 4 (L4) of mammalian neocortex plays a crucial role in cortical information processing, yet a complete census of its cell types and connectivity remains elusive. Using whole-cell recordings with morphological recovery, we identified one major excitatory and seven inhibitory types of neurons in L4 of adult mouse visual cortex (V1). Nearly all excitatory neurons were pyramidal and all somatostatin-positive (SOM+) non-fast-spiking neurons were Martinotti cells. In contrast, in somatosensory cortex (S1), excitatory neurons were mostly stellate and SOM+ neurons were non-Martinotti. These morphologically distinct SOM+ interneurons corresponded to different transcriptomic cell types and were differentially integrated into the local circuit with only S1 neurons receiving local excitatory input. We propose that cell-type specific circuit motifs, such as the Martinotti/pyramidal and non-Martinotti/stellate pairs, are optionally used across the cortex as building blocks to assemble cortical circuits.

scholarly journals A unique role for DNA (hydroxy)methylation in epigenetic regulation of human inhibitory neurons

2018 ◽  
Vol 4 (9) ◽  
pp. eaau6190 ◽  
Author(s):  
Alexey Kozlenkov ◽  
Junhao Li ◽  
Pasha Apontes ◽  
Yasmin L. Hurd ◽  
William M. Byne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Brain Cell ◽  
Inhibitory Neurons ◽  
Brain Diseases ◽  
Unique Role ◽  
Neuropsychiatric Diseases ◽  
Excitatory Neurons ◽  
Cell Type Specific

Brain function depends on interaction of diverse cell types whose gene expression and identity are defined, in part, by epigenetic mechanisms. Neuronal DNA contains two major epigenetic modifications, methylcytosine (mC) and hydroxymethylcytosine (hmC), yet their cell type–specific landscapes and relationship with gene expression are poorly understood. We report high-resolution (h)mC analyses, together with transcriptome and histone modification profiling, in three major cell types in human prefrontal cortex: glutamatergic excitatory neurons, medial ganglionic eminence–derived γ-aminobutyric acid (GABA)ergic inhibitory neurons, and oligodendrocytes. We detected a unique association between hmC and gene expression in inhibitory neurons that differed significantly from the pattern in excitatory neurons and oligodendrocytes. We also found that risk loci associated with neuropsychiatric diseases were enriched near regions of reduced hmC in excitatory neurons and reduced mC in inhibitory neurons. Our findings indicate differential roles for mC and hmC in regulation of gene expression in different brain cell types, with implications for the etiology of human brain diseases.

scholarly journals Single-cell transcriptomics characterizes cell types in the subventricular zone and uncovers molecular defects underlying impaired adult neurogenesis

2018 ◽  
Author(s):  
Vera Zywitza ◽  
Aristotelis Misios ◽  
Lena Bunatyan ◽  
Thomas E. Willnow ◽  
Nikolaus Rajewsky
Keyword(s):  
Single Cell ◽  
Adult Neurogenesis ◽  
Subventricular Zone ◽  
Single Cells ◽  
Cell Types ◽  
Neural Cell ◽  
Adult Brain ◽  
List Type ◽  
Cell Type ◽  
Cell Type Specific

SUMMARYNeural stem cells (NSCs) contribute to plasticity and repair of the adult brain. Niches harboring NSCs are crucial for regulating stem cell self-renewal and differentiation. We used single-cell RNA profiling to generate an unbiased molecular atlas of all cell types in the largest neurogenic niche of the adult mouse brain, the subventricular zone (SVZ). We characterized > 20 neural and non-neural cell types and gained insights into the dynamics of neurogenesis by predicting future cell states based on computational analysis of RNA kinetics. Furthermore, we apply our single-cell approach to mice lacking LRP2, an endocytic receptor required for SVZ maintenance. The number of NSCs and proliferating progenitors was significantly reduced. Moreover, Wnt and BMP4 signaling was perturbed. We provide a valuable resource for adult neurogenesis, insights into SVZ neurogenesis regulation by LRP2, and a proof-of-principle demonstrating the power of single-cell RNA-seq in pinpointing neural cell type-specific functions in loss-of-function models.HIGHLIGHTSunbiased single-cell transcriptomics characterizes adult NSCs and their nichecell type-specific signatures and marker genes for 22 SVZ cell typesFree online tool to assess gene expression across 9,804 single cellscell type-specific dysfunctions underlying impaired adult neurogenesis

scholarly journals Impact of regulatory variation across human iPSCs and differentiated cells

2016 ◽  
Author(s):  
Nicholas E. Banovich ◽  
Yang I. Li ◽  
Anil Raj ◽  
Michelle C. Ward ◽  
Peyton Greenside ◽  
...  
Keyword(s):  
Complex Disease ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Open Chromatin ◽  
Cell Type ◽  
Regulatory Variation ◽  
Differentiated Cells ◽  
Human Ipscs ◽  
Cell Type Specific ◽  
The Impact

AbstractInduced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that are otherwise difficult to access. We investigated the use of iPSCs and iPSC-derived cells to study the impact of genetic variation across different cell types and as models for studies of complex disease. We established a panel of iPSCs from 58 well-studied Yoruba lymphoblastoid cell lines (LCLs); 14 of these lines were further differentiated into cardiomyocytes. We characterized regulatory variation across individuals and cell types by measuring gene expression, chromatin accessibility and DNA methylation. Regulatory variation between individuals is lower in iPSCs than in the differentiated cell types, consistent with the intuition that developmental processes are generally canalized. While most cell type-specific regulatory quantitative trait loci (QTLs) lie in chromatin that is open only in the affected cell types, we found that 20% of cell type-specific QTLs are in shared open chromatin. Finally, we developed a deep neural network to predict open chromatin regions from DNA sequence alone and were able to use the sequences of segregating haplotypes to predict the effects of common SNPs on cell type-specific chromatin accessibility.

scholarly journals Layer 4 of mouse neocortex differs in cell types and circuit organization between sensory areas

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Federico Scala ◽  
Dmitry Kobak ◽  
Shen Shan ◽  
Yves Bernaerts ◽  
Sophie Laturnus ◽  
...  
Keyword(s):  
Building Blocks ◽  
Cell Types ◽  
Excitatory Input ◽  
Cortical Circuits ◽  
Excitatory Neurons ◽  
Layer 4 ◽  
Cell Type Specific ◽  
Fast Spiking ◽  
Mouse Visual Cortex ◽  
Whole Cell Recordings

Abstract Layer 4 (L4) of mammalian neocortex plays a crucial role in cortical information processing, yet a complete census of its cell types and connectivity remains elusive. Using whole-cell recordings with morphological recovery, we identified one major excitatory and seven inhibitory types of neurons in L4 of adult mouse visual cortex (V1). Nearly all excitatory neurons were pyramidal and all somatostatin-positive (SOM+) non-fast-spiking interneurons were Martinotti cells. In contrast, in somatosensory cortex (S1), excitatory neurons were mostly stellate and SOM+ interneurons were non-Martinotti. These morphologically distinct SOM+ interneurons corresponded to different transcriptomic cell types and were differentially integrated into the local circuit with only S1 neurons receiving local excitatory input. We propose that cell type specific circuit motifs, such as the Martinotti/pyramidal and non-Martinotti/stellate pairs, are used across the cortex as building blocks to assemble cortical circuits.

scholarly journals Stem-cell-ubiquitous genes spatiotemporally coordinate division through regulation of stem-cell-specific gene networks

2019 ◽  
Author(s):  
Natalie M Clark ◽  
Eli Buckner ◽  
Adam P Fisher ◽  
Emily C Nelson ◽  
Thomas T Nguyen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Gene Networks ◽  
Cell Types ◽  
Specific Gene ◽  
Cell Renewal ◽  
Cell Type ◽  
Stem Cell Maintenance ◽  
Differentiated Cells ◽  
Cell Type Specific ◽  
Stem Cell Type

AbstractStem cells are responsible for generating all of the differentiated cells, tissues, and organs in a multicellular organism and, thus, play a crucial role in cell renewal, regeneration, and organization. A number of stem cell type-specific genes have a known role in stem cell maintenance, identity, and/or division. Yet, how genes expressed across different stem cell types, referred here as stem-cell-ubiquitous genes, contribute to stem cell regulation is less understood. Here, we find that, in the Arabidopsis root, a stem-cell-ubiquitous gene, TESMIN-LIKE CXC2 (TCX2), controls stem cell division by regulating stem cell-type specific networks. Development of a mathematical model of TCX2 expression allowed us to show that TCX2 orchestrates the coordinated division of different stem cell types. Our results highlight that genes expressed across different stem cell types ensure cross-communication among cells, allowing them to divide and develop harmonically together.

scholarly journals Recent advances in understanding DNA replication: cell type–specific adaptation of the DNA replication program

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1351 ◽  
Author(s):  
Antoine Aze ◽  
Domenico Maiorano
Keyword(s):  
Cell Division ◽  
Dna Replication ◽  
Dna Synthesis ◽  
Genetic Diseases ◽  
Cell Types ◽  
Differentiated Cells ◽  
Undifferentiated Cells ◽  
Cell Type Specific ◽  
Division Cell ◽  
Different Cell Types

DNA replication is an essential process occurring prior to cell division. Cell division coupled to proliferation ensures the growth and renewal of a large variety of specialized cell types generated during embryonic development. Changes in the DNA replication program occur during development. Embryonic undifferentiated cells show a high replication rate and fast proliferation, whereas more differentiated cells are characterized by reduced DNA synthesis and a low proliferation rate. Hence, the DNA replication program must adapt to the specific features of cells committed to different fates. Recent findings on DNA synthesis regulation in different cell types open new perspectives for developing efficient and more adapted therapies to treat various diseases such as genetic diseases and cancer. This review will put the emphasis on recent progress made in this field.

Neuronal mRNA Translation in Addiction

2018 ◽  
Author(s):  
Emma Puighermanal ◽  
Emmanuel Valjent
Keyword(s):  
Structural Changes ◽  
Drugs Of Abuse ◽  
Mrna Translation ◽  
Cell Types ◽  
Behavioral Changes ◽  
Translational Machinery ◽  
Addictive Drugs ◽  
Specific Mrnas ◽  
Cell Type Specific ◽  
Future Work

Addictive drugs trigger persistent synaptic and structural changes in the neuronal reward circuits that are thought to underlie the development of drug-adaptive behavior. While transcriptional and epigenetic modifications are known to contribute to these circuit changes, accumulating evidence indicates that altered mRNA translation is also a key molecular mechanism. This chapter reviews recent studies demonstrating how addictive drugs alter protein synthesis and/or the translational machinery and how this leads to neuronal circuit remodeling and behavioral changes. Future work will determine precisely which neuronal circuits and cell types participate in these changes. The chapter summarizes current methodologies for identifying cell type-specific mRNAs whose translation is affected by drugs of abuse and gives recent examples of the mechanistic insights into addiction they provide.

scholarly journals scSorter: assigning cells to known cell types according to marker genes

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hongyu Guo ◽  
Jun Li
Keyword(s):  
Real Data ◽  
Cell Types ◽  
Exact Expression ◽  
Marker Genes ◽  
Specific Marker ◽  
Sequencing Data ◽  
Reference Dataset ◽  
Over Expression ◽  
Higher Power ◽  
Cell Type Specific

AbstractOn single-cell RNA-sequencing data, we consider the problem of assigning cells to known cell types, assuming that the identities of cell-type-specific marker genes are given but their exact expression levels are unavailable, that is, without using a reference dataset. Based on an observation that the expected over-expression of marker genes is often absent in a nonnegligible proportion of cells, we develop a method called scSorter. scSorter allows marker genes to express at a low level and borrows information from the expression of non-marker genes. On both simulated and real data, scSorter shows much higher power compared to existing methods.

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