Publications by authors named "Chelsea Marcho"

11 Publications

  • Page 1 of 1

Sperm DNA methylation mediates the association of male age on reproductive outcomes among couples undergoing infertility treatment.

Sci Rep 2021 Feb 5;11(1):3216. Epub 2021 Feb 5.

Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, 173A Goessmann, 686 North Pleasant Street, Amherst, MA, 01003, USA.

Parental age at time of offspring conception is increasing in developed countries. Advanced male age is associated with decreased reproductive success and increased risk of adverse neurodevelopmental outcomes in offspring. Mechanisms for these male age effects remain unclear, but changes in sperm DNA methylation over time is one potential explanation. We assessed genome-wide methylation of sperm DNA from 47 semen samples collected from male participants of couples seeking infertility treatment. We report that higher male age was associated with lower likelihood of fertilization and live birth, and poor embryo development (p < 0.05). Furthermore, our multivariable linear models showed male age was associated with alterations in sperm methylation at 1698 CpGs and 1146 regions (q < 0.05), which were associated with > 750 genes enriched in embryonic development, behavior and neurodevelopment among others. High dimensional mediation analyses identified four genes (DEFB126, TPI1P3, PLCH2 and DLGAP2) with age-related sperm differential methylation that accounted for 64% (95% CI 0.42-0.86%; p < 0.05) of the effect of male age on lower fertilization rate. Our findings from this modest IVF population provide evidence for sperm methylation as a mechanism of age-induced poor reproductive outcomes and identifies possible candidate genes for mediating these effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-80857-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864951PMC
February 2021

Aging-induced changes in sperm DNA methylation are modified by low dose of perinatal flame retardants.

Epigenomics 2021 Feb 6;13(4):285-297. Epub 2021 Jan 6.

Department of Environmental Health Sciences, School of Public Health & Health Sciences, University of Massachusetts, 686 North Pleasant Street, Amherst, MA 01003, USA.

Paternal age is increasing in developed countries. Understanding of aging-related epigenetic changes in sperm is needed as well as factors that modify such changes. Young pubertal and mature rats were exposed perinatally to vehicle or environmental xenobiotic 2,2',4,4'-tetrabromodiphenyl ether. Epididymal sperm was reduced representation bisulfite sequenced. Differentially methylated regions (DMRs) were identified via MethPipe. In control animals, 5319 age-dependent DMRs were identified. Age-related DMRs were enriched for embryonic development. In exposed rats, DNA methylation was higher in young and lower in mature animals then in controls. Sperm methylome undergoes significant age-dependent changes, which may represent a causal link between paternal age and offspring phenotype. Environmental xenobiotics can interfere with the natural process of epigenetic aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi-2020-0404DOI Listing
February 2021

Association between sperm mitochondarial DNA copy number and nuclear DNA methylation.

Epigenomics 2020 Dec 15;12(24):2141-2153. Epub 2020 Dec 15.

Department of Environmental Health Sciences, School of Public Health & Health Sciences, University of Massachusetts Amherst, 686 North Pleasant Street, Amherst, MA 01003, USA.

Accumulating evidence associates sperm mitochondria DNA copy number (mtDNAcn) with male infertility and reproductive success. However, the mechanism underlying mtDNAcn variation is largely unknown. Sperm mtDNAcn and genome-wide DNA methylation were assessed using triplex probe-based quantitative PCR and Illumina's 450K array, respectively. Multivariable models assessed the association between sperm mtDNAcn and DNA methylation profiles of 47 men seeking infertility treatment. candidate-gene approach showed sperm mtDNAcn was associated with 16 CpGs located at/near and genes. Unbiased genome-wide analysis revealed that sperm mtDNAcn was associated with 218 sperm differentially methylated regions (q < 0.05), which displayed predominantly (94%) increases in methylation. Findings suggest that DNA methylation may play a role in regulating sperm mtDNAcn.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi-2020-0253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857360PMC
December 2020

The preconception environment and sperm epigenetics.

Andrology 2020 07 21;8(4):924-942. Epub 2020 Jan 21.

Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, Massachusetts.

Background: Infertility is a common reproductive disorder, with male factor infertility accounting for approximately half of all cases. Taking a paternal perceptive, recent research has shown that sperm epigenetics, such as changes in DNA methylation, histone modification, chromatin structure, and noncoding RNA expression, can impact reproductive and offspring health. Importantly, environmental conditions during the preconception period has been demonstrated to shape sperm epigenetics.

Objectives: To provide an overview on epigenetic modifications that regulate normal gene expression and epigenetic remodeling that occurs during spermatogenesis, and to discuss the epigenetic alterations that may occur to the paternal germline as a consequence of preconception environmental conditions and exposures.

Materials And Methods: We examined published literature available on databases (PubMed, Google Scholar, ScienceDirect) focusing on adult male preconception environmental exposures and sperm epigenetics in epidemiologic studies and animal models.

Results: The preconception period is a sensitive developmental window in which a variety of exposures such as toxicants, nutrition, drugs, stress, and exercise, affects sperm epigenetics.

Discussion And Conclusion: Understanding the environmental legacy of the sperm epigenome during spermatogenesis will enhance our understanding of reproductive health and improve reproductive success and offspring well-being.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/andr.12753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346722PMC
July 2020

MED20 is essential for early embryogenesis and regulates NANOG expression.

Reproduction 2019 03;157(3):215-222

Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts, USA.

Mediator is an evolutionarily conserved multi-subunit complex, bridging transcriptional activators and repressors to the general RNA polymerase II (Pol II) initiation machinery. Though the Mediator complex is crucial for the transcription of almost all Pol II promoters in eukaryotic organisms, the phenotypes of individual Mediator subunit mutants are each distinct. Here, we report for the first time, the essential role of subunit MED20 in early mammalian embryo development. Although Med20 mutant mouse embryos exhibit normal morphology at E3.5 blastocyst stage, they cannot be recovered at early post-gastrulation stages. Outgrowth assays show that mutant blastocysts cannot hatch from the zona pellucida, indicating impaired blastocyst function. Assessments of cell death and cell lineage specification reveal that apoptosis, inner cell mass, trophectoderm and primitive endoderm markers are normal in mutant blastocysts. However, the epiblast marker NANOG is ectopically expressed in the trophectoderm of Med20 mutants, indicative of defects in trophoblast specification. These results suggest that MED20 specifically, and the Mediator complex in general, are essential for the earliest steps of mammalian development and cell lineage specification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/REP-18-0508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545164PMC
March 2019

Towards Functional Annotation of the Preimplantation Transcriptome: An RNAi Screen in Mammalian Embryos.

Sci Rep 2016 11 21;6:37396. Epub 2016 Nov 21.

Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA.

With readily available transcriptome-wide data, understanding the role of each expressed gene is an essential next step. Although RNAi technologies allow for genome-wide screens in cell culture, these approaches cannot replace strategies for discovery in the embryo. Here we present, for the first time, a knockdown screen in mouse preimplantation embryos. Early mammalian development encompasses dynamic cellular, molecular and epigenetic events that are largely conserved from mouse to man. We assayed 712 genes for requirements during preimplantation. We identified 59 genes required for successful development or outgrowth and implantation. We have characterized each phenotype and revealed cellular, molecular, and lineage specific defects following knockdown of transcript. Induced network analyses demonstrate this as a valid approach to identify networks of genes that play important roles during preimplantation. Our approach provides a robust and efficient strategy towards identification of novel phenotypes during mouse preimplantation and facilitates functional annotation of the mammalian transcriptome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep37396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116644PMC
November 2016

DIGIT Is a Conserved Long Noncoding RNA that Regulates GSC Expression to Control Definitive Endoderm Differentiation of Embryonic Stem Cells.

Cell Rep 2016 10;17(2):353-365

Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address:

Long noncoding RNAs (lncRNAs) exhibit diverse functions, including regulation of development. Here, we combine genome-wide mapping of SMAD3 occupancy with expression analysis to identify lncRNAs induced by activin signaling during endoderm differentiation of human embryonic stem cells (hESCs). We find that DIGIT is divergent to Goosecoid (GSC) and expressed during endoderm differentiation. Deletion of the SMAD3-occupied enhancer proximal to DIGIT inhibits DIGIT and GSC expression and definitive endoderm differentiation. Disruption of the gene encoding DIGIT and depletion of the DIGIT transcript reveal that DIGIT is required for definitive endoderm differentiation. In addition, we identify the mouse ortholog of DIGIT and show that it is expressed during development and promotes definitive endoderm differentiation of mouse ESCs. DIGIT regulates GSC in trans, and activation of endogenous GSC expression is sufficient to rescue definitive endoderm differentiation in DIGIT-deficient hESCs. Our study defines DIGIT as a conserved noncoding developmental regulator of definitive endoderm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2016.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120872PMC
October 2016

Nop2 is required for mammalian preimplantation development.

Mol Reprod Dev 2016 Feb 15;83(2):124-31. Epub 2015 Dec 15.

Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts.

Nucleolar protein 2 (NOP2) is evolutionarily conserved from yeast to human, and has been found to play an important role in accelerating cell proliferation, cell-cycle progression, and tumor aggressiveness. The expression pattern and function of Nop2 during early mammalian embryo development, however, has not been investigated. We identified Nop2 as an essential gene for development to the blastocyst stage while performing an RNA interference (RNAi)-based screen in mouse preimplantation embryos. Nop2 is expressed throughout preimplantation development, with highest mRNA and protein accumulation at the 8-cell and morula stages, respectively. RNAi-mediated knockdown of Nop2 results in embryos that arrest as morula. NOP2-deficient embryos exhibit reduced blastomere numbers, greatly increased apoptosis, and impaired cell-lineage specification. Furthermore, knockdown of Nop2 results in global reduction of all RNA species, including rRNA, small nuclear RNA, small nucleolar RNA, and mRNA. Taken together, our results demonstrate that Nop2 is an essential gene for blastocyst formation, and is required for RNA processing and/or stability in vivo during preimplantation embryo development in the mouse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mrd.22600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4903073PMC
February 2016

Epigenetic dynamics during preimplantation development.

Reproduction 2015 Sep 1;150(3):R109-20. Epub 2015 Jun 1.

Department of Veterinary and Animal ScienceUniversity of Massachusetts Amherst, 661 North Pleasant Street, Amherst, Massachusetts 01003, USA

Successful mammalian development requires descendants of single-cell zygotes to differentiate into diverse cell types even though they contain the same genetic material. Preimplantation dynamics are first driven by the necessity of reprogramming haploid parental epigenomes to reach a totipotent state. This process requires extensive erasure of epigenetic marks shortly after fertilization. During the few short days after formation of the zygote, epigenetic programs are established and are essential for the first lineage decisions and differentiation. Here we review the current understanding of DNA methylation and histone modification dynamics responsible for these early changes during mammalian preimplantation development. In particular, we highlight insights that have been gained through next-generation sequencing technologies comparing human embryos to other models as well as the recent discoveries of active DNA demethylation mechanisms at play during preimplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/REP-15-0180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529766PMC
September 2015

Tissue-specific regulation of Igf2r/Airn imprinting during gastrulation.

Epigenetics Chromatin 2015 14;8:10. Epub 2015 Mar 14.

Department of Veterinary and Animal Sciences, University of Massachusetts at Amherst, ISB 427M, 661 N. Pleasant Street, Amherst, MA 01003 USA.

Background: Appropriate epigenetic regulation of gene expression during lineage allocation and tissue differentiation is required for normal development. One example is genomic imprinting, which is defined as parent-of-origin mono-allelic gene expression. Imprinting is established largely due to epigenetic differences arriving in the zygote from sperm and egg haploid genomes. In the mouse, there are approximately 150 known imprinted genes, many of which occur in imprinted gene clusters that are regulated together. One imprinted cluster includes the maternally expressed Igf2r, Slc22a2, and Slc22a3 genes and the paternally expressed long non-coding RNA (lncRNA) Airn. Although it is known that Igf2r and Airn are reciprocally imprinted, the timing of imprinted expression and accompanying epigenetic changes have not been well characterized in vivo.

Results: Here we show lineage- and temporal-specific regulation of DNA methylation and histone modifications at the Igf2r/Airn locus correlating with differential establishment of imprinted expression during gastrulation. Our results show that Igf2r is expressed from both alleles in the E6.5 epiblast. After gastrulation commences, the locus becomes imprinted in the embryonic lineage with the lncRNA Airn expressed from the paternal allele and Igf2r restricted to maternal allele expression. We document differentially enriched allele-specific histone modifications in extraembryonic and embryonic tissues. We also document for the first time allele-specific spreading of DNA methylation during gastrulation concurrent with establishment of imprinted expression of Igf2r. Importantly, we show that imprinted expression does not change in the extraembryonic lineage even though maternal DMR2 methylation spreading does occur, suggesting distinct mechanisms at play in embryonic and extraembryonic lineages.

Conclusions: These results indicate that similar to preimplantation, gastrulation represents a window of dynamic lineage-specific epigenetic regulation in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13072-015-0003-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410455PMC
April 2015

RLIM is dispensable for X-chromosome inactivation in the mouse embryonic epiblast.

Nature 2014 Jul 25;511(7507):86-9. Epub 2014 May 25.

1] Program in Gene Function and Expression, University of Massachusetts Medical School (UMMS), Worcester, Massachusetts 01605, USA [2] Program in Molecular Medicine, UMMS, Worcester, Massachusetts 01605, USA.

In female mice, two forms of X-chromosome inactivation (XCI) ensure the selective silencing of female sex chromosomes during mouse embryogenesis. Beginning at the four-cell stage, imprinted XCI (iXCI) exclusively silences the paternal X chromosome. Later, around implantation, epiblast cells of the inner cell mass that give rise to the embryo reactivate the paternal X chromosome and undergo a random form of XCI (rXCI). Xist, a long non-coding RNA crucial for both forms of XCI, is activated by the ubiquitin ligase RLIM (also known as Rnf12). Although RLIM is required for triggering iXCI in mice, its importance for rXCI has been controversial. Here we show that RLIM levels are downregulated in embryonic cells undergoing rXCI. Using mouse genetics we demonstrate that female cells lacking RLIM from pre-implantation stages onwards show hallmarks of XCI, including Xist clouds and H3K27me3 foci, and have full embryogenic potential. These results provide evidence that RLIM is dispensable for rXCI, indicating that in mice an RLIM-independent mechanism activates Xist in the embryo proper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature13286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105192PMC
July 2014