scholarly journals EHMT2 Controls Transcriptional Noise and the Developmental Switch after Gastrulation in the Mouse Embryo

2021 ◽  
Author(s):  
Tie-Bo Zeng ◽  
Nicholas Pierce ◽  
Ji Liao ◽  
Purnima Singh ◽  
Wanding Zhou ◽  
...  
Keyword(s):  
Muscle Development ◽  
Striated Muscle ◽  
Normal Embryo ◽  
Developmentally Delayed ◽  
Gene Encoding ◽  
Repeat Elements ◽  
Somite Stage ◽  
Transcriptional Variation ◽  
Important Regulator ◽  
Developmental Switch

Embryos that carry zygotic or parental mutations in Ehmt2, the gene encoding the main euchromatic histone H3K9 methyltransferase, EHMT2, exhibit variable developmental delay. We asked the question whether the delayed embryo is different transcriptionally from the normally developing embryo when they reach the same developmental stage. We collected embryos carrying a series of genetic deficiencies in the Ehmt2 gene and performed total RNA sequencing of somite stage-matched individual embryos. We applied novel four-way comparisons to detect differences between normal versus deficient embryos, and between 12-somite and 6-somite embryos. Importantly, we also identified developmental changes in transcription that only occur during the development of the normal embryo. We found that at the 6-somite stage, gastrulation-specific genes were not precisely turned off in the Ehmt2-/- embryos, and genes involved in organ growth, connective tissue development, striated muscle development, muscle differentiation, and cartilage development were not precisely switched on in the Ehmt2-/- embryos. Zygotic EHMT2 reduced transcriptional variation of developmental switch genes and at some repeat elements at the six-somite stage embryos. Maternal EHMT2-mutant embryos also displayed great transcriptional variation consistent with their variable survival, but transcription was normal in developmentally delayed parental haploinsufficient embryos, consistent with their good prospects. Global profiling of transposable elements in the embryo revealed that specific repeat classes responded to EHMT2. DNA methylation was specifically targeted by EHMT2 to LTR repeats, mostly ERVKs. Long noncoding transcripts initiated from those misregulated driver repeats in Ehmt2-/- embryos, and extended to several hundred kilobases, encompassing a multitude of additional, similarly misexpressed passenger repeats. These findings establish EHMT2 as an important regulator of the transition between gastrulation programs and organ specification programs and of variability.

scholarly journals EHMT2 suppresses the variation of transcriptional switches in the mouse embryo

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009908
Author(s):  
Tie-Bo Zeng ◽  
Nicholas Pierce ◽  
Ji Liao ◽  
Purnima Singh ◽  
Kin Lau ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Muscle Development ◽  
Striated Muscle ◽  
Wild Type ◽  
Repeat Elements ◽  
Developmental Variation ◽  
Somite Stage ◽  
Developmental Progression ◽  
Transcriptional Variation ◽  
The Difference

EHMT2 is the main euchromatic H3K9 methyltransferase. Embryos with zygotic, or maternal mutation in the Ehmt2 gene exhibit variable developmental delay. To understand how EHMT2 prevents variable developmental delay we performed RNA sequencing of mutant and somite stage-matched normal embryos at 8.5–9.5 days of gestation. Using four-way comparisons between delayed and normal embryos we clarified what it takes to be normal and what it takes to develop. We identified differentially expressed genes, for example Hox genes that simply reflected the difference in developmental progression of wild type and the delayed mutant uterus-mate embryos. By comparing wild type and zygotic mutant embryos along the same developmental window we detected a role of EHMT2 in suppressing variation in the transcriptional switches. We identified transcription changes where precise switching during development occurred only in the normal but not in the mutant embryo. At the 6-somite stage, gastrulation-specific genes were not precisely switched off in the Ehmt2−/− zygotic mutant embryos, while genes involved in organ growth, connective tissue development, striated muscle development, muscle differentiation, and cartilage development were not precisely switched on. The Ehmt2mat−/+ maternal mutant embryos displayed high transcriptional variation consistent with their variable survival. Variable derepression of transcripts occurred dominantly in the maternally inherited allele. Transcription was normal in the parental haploinsufficient wild type embryos despite their delay, consistent with their good prospects. Global profiling of transposable elements revealed EHMT2 targeted DNA methylation and suppression at LTR repeats, mostly ERVKs. In Ehmt2−/− embryos, transcription over very long distances initiated from such misregulated ‘driver’ ERVK repeats, encompassing a multitude of misexpressed ‘passenger’ repeats. In summary, EHMT2 reduced transcriptional variation of developmental switch genes and developmentally switching repeat elements at the six-somite stage embryos. These findings establish EHMT2 as a suppressor of transcriptional and developmental variation at the transition between gastrulation and organ specification.

scholarly journals Transcription Landscape of the Early Developmental Biology in Pigs

Animals ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1443
Author(s):  
Susana A. Teixeira ◽  
Daniele B. D. Marques ◽  
Thaís C. Costa ◽  
Haniel C. Oliveira ◽  
Karine A. Costa ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Muscle Development ◽  
Neuronal Development ◽  
Striated Muscle ◽  
Prenatal Development ◽  
Sequencing Analysis ◽  
Neuronal System ◽  
Matrix Organization ◽  
Early Developmental ◽  
Transcriptional Landscape

Since pre- and postnatal development are programmed during early prenatal life, studies addressing the complete transcriptional landscape during organogenesis are needed. Therefore, we aimed to disentangle differentially expressed (DE) genes between fetuses (at 35 days old) and embryos (at 25 days old) through RNA-sequencing analysis using the pig as model. In total, 1705 genes were DE, including the top DE IBSP, COL6A6, HBE1, HBZ, HBB, and NEUROD6 genes, which are associated with developmental transition from embryos to fetuses, such as ossification, skeletal muscle development, extracellular matrix organization, cardiovascular system, erythrocyte differentiation, and neuronal system. In pathway analysis, embryonic development highlighted those mainly related to morphogenic signaling and cell interactions, which are crucial for transcriptional control during the establishment of the main organs in early prenatal development, while pathways related to myogenesis, neuronal development, and cardiac and striated muscle contraction were enriched for fetal development, according to the greater complexity of organs and body structures at this developmental stage. Our findings provide an exploratory and informative transcriptional landscape of pig organogenesis, which might contribute to further studies addressing specific developmental events in pigs and in other mammals.

scholarly journals Origins, potency, and heterogeneity of skeletal muscle fibro-adipogenic progenitors—time for new definitions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Osvaldo Contreras ◽  
Fabio M. V. Rossi ◽  
Marine Theret
Keyword(s):  
Extracellular Matrix ◽  
Muscle Development ◽  
Striated Muscle ◽  
Body Movement ◽  
Well Being ◽  
Lineage Tracing ◽  
Extracellular Matrix Components ◽  
Main Components ◽  
Muscle Homeostasis ◽  
Activated Fibroblasts

AbstractStriated muscle is a highly plastic and regenerative organ that regulates body movement, temperature, and metabolism—all the functions needed for an individual’s health and well-being. The muscle connective tissue’s main components are the extracellular matrix and its resident stromal cells, which continuously reshape it in embryonic development, homeostasis, and regeneration. Fibro-adipogenic progenitors are enigmatic and transformative muscle-resident interstitial cells with mesenchymal stem/stromal cell properties. They act as cellular sentinels and physiological hubs for adult muscle homeostasis and regeneration by shaping the microenvironment by secreting a complex cocktail of extracellular matrix components, diffusible cytokines, ligands, and immune-modulatory factors. Fibro-adipogenic progenitors are the lineage precursors of specialized cells, including activated fibroblasts, adipocytes, and osteogenic cells after injury. Here, we discuss current research gaps, potential druggable developments, and outstanding questions about fibro-adipogenic progenitor origins, potency, and heterogeneity. Finally, we took advantage of recent advances in single-cell technologies combined with lineage tracing to unify the diversity of stromal fibro-adipogenic progenitors. Thus, this compelling review provides new cellular and molecular insights in comprehending the origins, definitions, markers, fate, and plasticity of murine and human fibro-adipogenic progenitors in muscle development, homeostasis, regeneration, and repair.

A C. elegans E/Daughterless bHLH protein marks neuronal but not striated muscle development

Development ◽  
1997 ◽  
Vol 124 (11) ◽  
pp. 2179-2189 ◽  
Author(s):  
M. Krause ◽  
M. Park ◽  
J.M. Zhang ◽  
J. Yuan ◽  
B. Harfe ◽  
...  
Keyword(s):  
Muscle Development ◽  
Striated Muscle ◽  
Bhlh Protein ◽  
E Proteins ◽  
Mobility Shift ◽  
C Elegans ◽  
Helix Loop Helix ◽  
Neuronal Precursors ◽  
Gel Mobility Shift

The E proteins of mammals, and the related Daughterless (DA) protein of Drosophila, are ubiquitously expressed helix-loop-helix (HLH) transcription factors that play a role in many developmental processes. We report here the characterization of a related C. elegans protein, CeE/DA, which has a dynamic and restricted distribution during development. CeE/DA is present embryonically in neuronal precursors, some of which are marked by promoter activity of a newly described Achaete-scute-like gene hlh-3. In contrast, we have been unable to detect CeE/DA in CeMyoD-positive striated muscle cells. In vitro gel mobility shift analysis detects dimerization of CeE/DA with HLH-3 while efficient interaction of CeE/DA with CeMyoD is not seen. These studies suggest multiple roles for CeE/DA in C. elegans development and provide evidence that both common and alternative strategies have evolved for the use of related HLH proteins in controlling cell fates in different species.

The role of the NK-homeobox gene slouch (S59) in somatic muscle patterning

Development ◽  
1999 ◽  
Vol 126 (20) ◽  
pp. 4525-4535 ◽  
Author(s):  
S. Knirr ◽  
N. Azpiazu ◽  
M. Frasch
Keyword(s):  
Muscle Development ◽  
Ectopic Expression ◽  
Homeobox Gene ◽  
Drosophila Embryo ◽  
Loss Of Function ◽  
Cell Fates ◽  
Somatic Muscle ◽  
Gene Encoding ◽  
Body Wall Muscles ◽  
Founder Cells

In the Drosophila embryo, a distinct class of myoblasts, designated as muscle founders, prefigures the mature pattern of somatic body wall muscles. Each founder cell appears to be instrumental in generating a single larval muscle with a defined identity. The NK homeobox gene S59 was the first of a growing number of proposed ‘identity genes’ that have been found to be expressed in stereotyped patterns in specific subsets of muscle founders and their progenitor cells and are thought to control their developmental fates. In the present study, we describe the effects of gain- and loss-of-function experiments with S59. We find that a null mutation in the gene encoding S59, which we have named slouch (slou), disrupts the development of all muscles that are derived from S59-expressing founder cells. The observed phenotypes upon mutation and ectopic expression of slouch include transformations of founder cell fates, thus confirming that slouch (S59) functions as an identity gene in muscle development. These fate transformations occur between sibling founder cells as well as between neighboring founders that are not lineage-related. In the latter case, we show that slouch (S59) activity is required cell-autonomously to repress the expression of ladybird (lb) homeobox genes, thereby preventing specification along the lb pathway. Together, these findings provide new insights into the regulatory interactions that establish the somatic muscle pattern.

Caenorhabditis elegans twist plays an essential role in non-striated muscle development

Development ◽  
2000 ◽  
Vol 127 (10) ◽  
pp. 2041-2051 ◽  
Author(s):  
A.K. Corsi ◽  
S.A. Kostas ◽  
A. Fire ◽  
M. Krause
Keyword(s):  
Caenorhabditis Elegans ◽  
Essential Role ◽  
Muscle Development ◽  
Target Genes ◽  
Striated Muscle ◽  
Egg Laying ◽  
Bhlh Transcription Factor ◽  
Striated Muscles ◽  
Downstream Target ◽  
Mesodermal Development

The basic helix-loop-helix (bHLH) transcription factor Twist plays a role in mesodermal development in both invertebrates and vertebrates. In an effort to understand the role of the unique Caenorhabditis elegans Twist homolog, hlh-8, we analyzed mesodermal development in animals with a deletion in the hlh-8 locus. This deletion was predicted to represent a null allele because the HLH domain is missing and the reading frame for the protein is disrupted. Animals lacking CeTwist function were constipated and egg-laying defective. Both of these defects were rescued in transgenic mutant animals expressing wild-type hlh-8. Observing a series of mesoderm-specific markers allowed us to characterize the loss of hlh-8 function more thoroughly. Our results demonstrate that CeTwist performs an essential role in the proper development of a subset of mesodermal tissues in C. elegans. We found that CeTwist was required for the formation of three out of the four non-striated enteric muscles born in the embryo. In contrast, CeTwist was not required for the formation of the embryonically derived striated muscles. Most of the post-embryonic mesoderm develops from a single lineage. CeTwist was necessary for appropriate patterning in this lineage and was required for expression of two downstream target genes, but was not required for the expression of myosin, a marker of differentiation. Our results suggest that mesodermal patterning by Twist is an evolutionarily conserved function.

scholarly journals TIN2 Functions with TPP1/POT1 To Stimulate Telomerase Processivity

2019 ◽  
Vol 39 (21) ◽  
Author(s):  
Alexandra M. Pike ◽  
Margaret A. Strong ◽  
John Paul T. Ouyang ◽  
Carol W. Greider
Keyword(s):  
Telomere Length ◽  
Telomerase Activity ◽  
Human Cells ◽  
Short Telomere ◽  
Gene Encoding ◽  
Important Regulator

ABSTRACT TIN2 is an important regulator of telomere length, and mutations in TINF2, the gene encoding TIN2, cause short-telomere syndromes. While the genetics underscore the importance of TIN2, the mechanism through which TIN2 regulates telomere length remains unclear. Here, we tested the effects of human TIN2 on telomerase activity. We identified a new isoform in human cells, TIN2M, that is expressed at levels similar to those of previously studied TIN2 isoforms. All three TIN2 isoforms localized to and maintained telomere integrity in vivo, and localization was not disrupted by telomere syndrome mutations. Using direct telomerase activity assays, we discovered that TIN2 stimulated telomerase processivity in vitro. All of the TIN2 isoforms stimulated telomerase to similar extents. Mutations in the TPP1 TEL patch abrogated this stimulation, suggesting that TIN2 functions with TPP1/POT1 to stimulate telomerase processivity. We conclude from our data and previously published work that TIN2/TPP1/POT1 is a functional shelterin subcomplex.

Splicing transitions of the anchoring protein ENH during striated muscle development

2012 ◽  
Vol 421 (2) ◽  
pp. 232-238 ◽  
Author(s):  
Jumpei Ito ◽  
Taiki Hashimoto ◽  
Sho Nakamura ◽  
Yusuke Aita ◽  
Tomoko Yamazaki ◽  
...  
Keyword(s):  
Muscle Development ◽  
Striated Muscle ◽  
Anchoring Protein
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