Epigenetic factors coordinate intestinal development

AbstractIntestinal epithelium development depends on epigenetic modifications, but whether that is also the case for other intestinal tract cell types remains unclear. We found that functional loss of a DNA methylation machinery component, ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1), leads to reduced enteric neuron number, changes in neuronal morphology, and severe intestinal smooth muscle disruption. Genetic chimeras revealed that Uhrf1 functions both cell-autonomously in enteric neuron progenitors and cell-non-autonomously in surrounding intestinal cells. Uhrf1 recruits the DNA methyltransferase Dnmt1 to unmethylated DNA during replication. Dnmt1 is also expressed in enteric neuron and smooth muscle progenitors. dnmt1 mutants show a strong reduction in enteric neuron number and disrupted intestinal smooth muscle. Because dnmt1;uhrf1 double mutants have a similar phenotype to dnmt1 and uhrf1 single mutants, Dnmt1 and Uhrf1 must function together during enteric neuron and intestinal muscle development. This work shows that genes controlling epigenetic modifications are important in coordinating intestinal tract development, provides the first demonstration that these genes are important in ENS development, and advances uhrf1 and dnmt1 as potential new Hirschsprung disease candidates.SummaryThis work provides evidence that DNA methylation factors are important in all cell types that contribute to development of a functional intestine.

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Epigenetic modifications in brain and immune cells of multiple sclerosis patients

Multiple Sclerosis Journal ◽

10.1177/1352458517737389 ◽

2018 ◽

Vol 24 (1) ◽

pp. 69-74 ◽

Cited By ~ 12

Author(s):

Kamilah Castro ◽

Patrizia Casaccia

Keyword(s):

Multiple Sclerosis ◽

Dna Methylation ◽

Histone Acetylation ◽

Cell Function ◽

Cell Types ◽

Epigenetic Modifications ◽

Post Translational Modification ◽

Inflammatory Phenotype ◽

Cellular Specificity ◽

Multiple Sclerosis Patients

Multiple sclerosis (MS) is a debilitating neurological disease whose onset and progression are influenced by the interplay of genetic and environmental factors. Epigenetic modifications, which include post-translational modification of the histones and DNA, are considered mediators of gene–environment interactions and a growing body of evidence suggests that they play an important role in MS pathology and could be potential therapeutic targets. Since epigenetic events regulate transcription of different genes in a cell type–specific fashion, we caution on the distinct functional consequences that targeting the same epigenetic modifications might have in distinct cell types. In this review, we primarily focus on the role of histone acetylation and DNA methylation on oligodendrocyte and T-cell function and its potential implications for MS. We find that decreased histone acetylation and increased DNA methylation in oligodendrocyte lineage (OL) cells enhance myelin repair, which is beneficial for MS, while the same epigenetic processes in T cells augment their pro-inflammatory phenotype, which can exacerbate disease severity. In conclusion, epigenetic-based therapies for MS may have great value but only when cellular specificity is taken into consideration.

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Zebrafish enteric neuron formation corresponds to smooth muscle development

Developmental Biology ◽

10.1016/j.ydbio.2007.03.652 ◽

2007 ◽

Vol 306 (1) ◽

pp. 420

Author(s):

Kenneth N. Wallace ◽

Tasha Olden ◽

Sarah Beckman

Keyword(s):

Smooth Muscle ◽

Muscle Development ◽

Enteric Neuron

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HRC Is a Direct Transcriptional Target of MEF2 during Cardiac, Skeletal, and Arterial Smooth Muscle Development In Vivo

Molecular and Cellular Biology ◽

10.1128/mcb.24.9.3757-3768.2004 ◽

2004 ◽

Vol 24 (9) ◽

pp. 3757-3768 ◽

Cited By ~ 39

Author(s):

Joshua P. Anderson ◽

Evdokia Dodou ◽

Analeah B. Heidt ◽

Sarah J. De Val ◽

Eric J. Jaehnig ◽

...

Keyword(s):

Smooth Muscle ◽

Calcium Binding ◽

Muscle Development ◽

Serum Response Factor ◽

Cell Types ◽

Transcriptional Enhancer ◽

Arterial Smooth Muscle ◽

Conserved Sequence ◽

Transcriptional Target

ABSTRACT The HRC gene encodes the histidine-rich calcium-binding protein, which is found in the lumen of the junctional sarcoplasmic reticulum (SR) of cardiac and skeletal muscle and within calciosomes of arterial smooth muscle. The expression of HRC in cardiac, skeletal, and smooth muscle raises the possibility of a common transcriptional mechanism governing its expression in all three muscle cell types. In this study, we identified a transcriptional enhancer from the HRC gene that is sufficient to direct the expression of lacZ in the expression pattern of endogenous HRC in transgenic mice. The HRC enhancer contains a small, highly conserved sequence that is required for expression in all three muscle lineages. Within this conserved region is a consensus site for myocyte enhancer factor 2 (MEF2) proteins that we show is bound efficiently by MEF2 and is required for transgene expression in all three muscle lineages in vivo. Furthermore, the entire HRC enhancer sequence lacks any discernible CArG motifs, the binding site for serum response factor (SRF), and we show that the enhancer is not activated by SRF. Thus, these studies identify the HRC enhancer as the first MEF2-dependent, CArG-independent transcriptional target in smooth muscle and represent the first analysis of the transcriptional regulation of an SR gene in vivo.

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Understanding the Relevance of DNA Methylation Changes in Immune Differentiation and Disease

Genes ◽

10.3390/genes11010110 ◽

2020 ◽

Vol 11 (1) ◽

pp. 110 ◽

Cited By ~ 7

Author(s):

Carlos de la Calle-Fabregat ◽

Octavio Morante-Palacios ◽

Esteban Ballestar

Keyword(s):

Dna Methylation ◽

Cell Types ◽

Epigenetic Modifications ◽

Human Organism ◽

Cell Phenotype ◽

Effector Cells ◽

Technological Advances ◽

And Function ◽

Different Cell Types ◽

External Stimuli

Immune cells are one of the most complex and diverse systems in the human organism. Such diversity implies an intricate network of different cell types and interactions that are dependently interconnected. The processes by which different cell types differentiate from progenitors, mature, and finally exert their function requires an orchestrated succession of molecular processes that determine cell phenotype and function. The acquisition of these phenotypes is highly dependent on the establishment of unique epigenetic profiles that confer identity and function on the various types of effector cells. These epigenetic mechanisms integrate microenvironmental cues into the genome to establish specific transcriptional programs. Epigenetic modifications bridge environment and genome regulation and play a role in human diseases by their ability to modulate physiological programs through external stimuli. DNA methylation is one of the most ubiquitous, stable, and widely studied epigenetic modifications. Recent technological advances have facilitated the generation of a vast amount of genome-wide DNA methylation data, providing profound insights into the roles of DNA methylation in health and disease. This review considers the relevance of DNA methylation to immune system cellular development and function, as well as the participation of DNA methylation defects in immune-mediated pathologies, illustrated by selected paradigmatic diseases.

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Laminin α5 chain is required for intestinal smooth muscle development

Developmental Biology ◽

10.1016/s0012-1606(03)00254-9 ◽

2003 ◽

Vol 260 (2) ◽

pp. 376-390 ◽

Cited By ~ 51

Author(s):

Anne-Laure Bolcato-Bellemin ◽

Olivier Lefebvre ◽

Christiane Arnold ◽

Lydia Sorokin ◽

Jeffrey H Miner ◽

...

Keyword(s):

Smooth Muscle ◽

Muscle Development ◽

Intestinal Smooth Muscle

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Selective demethylation of two CpG sites causes postnatal activation of the Dao gene and consequent removal of d-serine within the mouse cerebellum

Clinical Epigenetics ◽

10.1186/s13148-019-0732-z ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 7

Author(s):

Mariella Cuomo ◽

Simona Keller ◽

Daniela Punzo ◽

Tommaso Nuzzo ◽

Ornella Affinito ◽

...

Keyword(s):

Amino Acids ◽

Dna Methylation ◽

Single Molecule ◽

Developmental Stages ◽

Cell Types ◽

Epigenetic Modifications ◽

Specific Cell ◽

Cpg Sites ◽

Brain Levels ◽

Mouse Cerebellum

Abstract Background Programmed epigenetic modifications occurring at early postnatal brain developmental stages may have a long-lasting impact on brain function and complex behavior throughout life. Notably, it is now emerging that several genes that undergo perinatal changes in DNA methylation are associated with neuropsychiatric disorders. In this context, we envisaged that epigenetic modifications during the perinatal period may potentially drive essential changes in the genes regulating brain levels of critical neuromodulators such as d-serine and d-aspartate. Dysfunction of this fine regulation may contribute to the genesis of schizophrenia or other mental disorders, in which altered levels of d-amino acids are found. We recently demonstrated that Ddo, the d-aspartate degradation gene, is actively demethylated to ultimately reduce d-aspartate levels. However, the role of epigenetics as a mechanism driving the regulation of appropriate d-ser levels during brain development has been poorly investigated to date. Methods We performed comprehensive ultradeep DNA methylation and hydroxymethylation profiling along with mRNA expression and HPLC-based d-amino acids level analyses of genes controlling the mammalian brain levels of d-serine and d-aspartate. DNA methylation changes occurring in specific cerebellar cell types were also investigated. We conducted high coverage targeted bisulfite sequencing by next-generation sequencing and single-molecule bioinformatic analysis. Results We report consistent spatiotemporal modifications occurring at the Dao gene during neonatal development in a specific brain region (the cerebellum) and within specific cell types (astrocytes) for the first time. Dynamic demethylation at two specific CpG sites located just downstream of the transcription start site was sufficient to strongly activate the Dao gene, ultimately promoting the complete physiological degradation of cerebellar d-serine a few days after mouse birth. High amount of 5′-hydroxymethylcytosine, exclusively detected at relevant CpG sites, strongly evoked the occurrence of an active demethylation process. Conclusion The present investigation demonstrates that robust and selective demethylation of two CpG sites is associated with postnatal activation of the Dao gene and consequent removal of d-serine within the mouse cerebellum. A single-molecule methylation approach applied at the Dao locus promises to identify different cell-type compositions and functions in different brain areas and developmental stages.

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