Jesse Mager

Jesse Mager, Ph.D.

Associate Professor

 

 

Office phone: 413-545-7368

Lab phone: 413-545-2339

Fax: 413-545-6326

Email: jmager [at] vasci [dot] umass [dot] edu

Office location: 427M ISB

Ph.D.: University of North Carolina
Postdoc Training: University of Pennsylvania

Classes:
ANIML SCI 311 - Animal Genetics
ANIML SCI 697J - Cells, Genes and Development
ANIML SCI 795A - Journal Club: Cells, Genes & Development

Developmental Epigenetics

Comrehensive genome sequencing has the potential to dramatically improve our understanding of the genetic underpinnings of normal biology and disease states. Uncovering how complex genomes are epigenetically modified and identification of the protein and RNA mediators responsible is a critical next step towards understanding the dynamic changes that occur throughout development and differentiation. My interests lie in understanding this epigenetic regulation of mammalian genomes, and we use the earliest stages of mouse development as a model system. Although brief in time, preimplantation development is an extremely dynamic period during which major epigenetic remodeling occurs, and the very first cell fate decisions are made. These key biological processes require global, yet exquisitely precise chromatin remodeling. We utilize various RNAi approaches towards identification of genes that regulate these earliest epigenetic decisions that occur during oogenesis and preimplantation development.

Identification of dynamic preimplantation expression patterns

Discovery of genes with dynamic expression patterns.Along with the genome sequences now available, extraordinary amounts of expression data are rapidly being produced. Several reports have defined large expression data sets during preimplantation development. We have used this information to assemble and validate lists of candidate genes with expression patterns that suggest important roles during preimplantation. Of particular interest are two expression patterns - genes which are expressed only during cleavage stages (A-P-A in figure), and those which are expressed in the egg and 1 cell zygote, but not thereafter (P-A-A). As these two expression patterns suggest roles during distinct developmental windows we use different approaches to assess the function of these genes.

Preimplantation RNAi and epigenetic reporters

Epigenetic regulation during preimplantation development begins with the remodeling of egg and sperm haploid genomes prior to pronuclear fusion. By the time of blastocyst formation (3.5 days post fertilization in the mouse), differential chromatin structure has been established at sites throughout the genome, including parent of origin imprinted domains as well as trophoblast and ICM specific gene expression. To capitalize on the manipulability of this early window of epigenetic reorganization, we knock-down candidate transcripts by injecting or electroporating long dsRNAs into single cell embryos, followed by in-vitro culture until the blastocyst stage.

Genome imprinting is an epigenetic mechanism resulting in differential transcriptional activity between the two parental alleles. It is well established that differential chromatin structure accompanies this parent of origin gene expression. More specifically, DNA hypo/hyper-methylation, and core histone modifications (acetylation/methylation) differ between the active and silent alleles. Disruption of any one of these chromatin modifications may result in loss of imprinting at particular loci, making imprinted genes sensitive “reporters” of epigenetic regulatory mechanisms. In addition to harboring the necessary polymorphisms for imprinting and X inactivation assays, the mouse strains used for the phenotypic screen also carry an EGFP transgene driven by the Oct4 promoter, which is specifically expressed in the ICM at the blastocyst stage. We therefore screen for loss of imprinting, defects in trophoblast/ICM differentiation, as well as developmental arrest and morphological abnormalities all within the same embryos.

Preimplantation RNAi screen overflow

Transgenic RNAi during gametogenesis:

Another approach that our lab utilizes is the creation of mice that carry transgenes that knock-down genes of interest specifically in developing germ cells (egg and sperm). This approach allows us to explore the role of epigenetic regulatory genes prior to fertilization during germ cell development – a time when genome wide alterations are required to erase any and all somatic cell modifications, and prepare the diploid cell nucleus for the process of meiosis and haploid gamete production. This transgenic RNAi approach allows for allelic series of mice to be generated with each founding transgene eliciting various levels of gene specific knock down. Importantly, we have already generated phenotypes not only during oogenesis, but during preimplantation as well – indicating that this approach can identify gene functions which are truly epigenetic in origin –loss of function during oogenesis that result in defects several days later during preimplantation development.

We currently generate transgenic RNAi constructs that act during oocyte development, and are pursuing similar approaches in the male germ line to specifically knock down genes during spermatogenesis.

Shin JD, Wallingford MC, Gallant J, Marcho C, Jiao B, Byron M, Bossenz M, Lawrence JB, Jones SN, Mager J et al..  2014.  RLIM is dispensable for X-chromosome inactivation in the mouse embryonic epiblast.. Nature. 511(7507):86-9.
Wertheimer E, Krapf D, Vega-Beltran JL, Sánchez-Cárdenas C, Navarrete F, Haddad D, Escoffier J, Salicioni AM, Levin LR, Buck J et al..  2013.  Compartmentalization of Distinct cAMP Signaling Pathways in Mammalian Sperm.. J Biol Chem.
Wallingford MC, Angelo JR, Mager J.  2013.  Morphogenetic analysis of peri-implantation development.. Dev Dyn. 242(9):1110-20.
Rhee S, Guerrero-Zayas M-I, Wallingford MC, Ortiz-Pineda P, Mager J, Tremblay KD.  2013.  Visceral endoderm expression of Yin-Yang1 (YY1) is required for VEGFA maintenance and yolk sac development.. PLoS One. 8(3):e58828.
Maserati M, Dai X, Walentuk M, Mager J.  2012.  Identification of 4 genes required for mammalian blastocyst formation.. Zygote. In Press
Zhang K, Dai X, Wallingford MC, Mager J.  2012.  Depletion of Suds3 reveals an essential role in early lineage specification.. Developmental biology.
Griffith GJ, Trask MC, Hiller J, Walentuk M, Pawlak JB, Tremblay KD, Mager J.  2011.  Yin-yang1 is required in the mammalian oocyte for follicle expansion.. Biology of reproduction. 84(4):654-63.
Maserati M, Walentuk M, Dai X, Holston O, Adams D, Mager J.  2011.  Wdr74 is required for blastocyst formation in the mouse.. PloS one. 6(7):e22516.
Trask MC, Mager J.  2011.  Complexity of polycomb group function: diverse mechanisms of target specificity.. Journal of cellular physiology. 226(7):1719-21.
Weaver JR, Sarkisian G, Krapp C, Mager J, Mann MRW, Bartolomei MS.  2010.  Domain-specific response of imprinted genes to reduced DNMT1.. Molecular and cellular biology. 30(16):3916-28.
Malcuit C, Trask MC, Santiago L, Beaudoin E, Tremblay KD, Mager J.  2009.  Identification of novel oocyte and granulosa cell markers.. Gene expression patterns : GEP. 9(6):404-10.
Rivera RM, Stein P, Weaver JR, Mager J, Schultz RM, Bartolomei MS.  2008.  Manipulations of mouse embryos prior to implantation result in aberrant expression of imprinted genes on day 9.5 of development.. Human molecular genetics. 17(1):1-14.
Yoon S-Y, Jellerette T, Salicioni AM, Lee HC, Yoo M-S, Coward K, Parrington J, Grow D, Cibelli JB, Visconti PE et al..  2008.  Human sperm devoid of PLC, zeta 1 fail to induce Ca(2+) release and are unable to initiate the first step of embryo development.. The Journal of clinical investigation. 118(11):3671-81.
Mager J, Schultz RM, Brunk BP, Bartolomei MS.  2006.  Identification of candidate maternal-effect genes through comparison of multiple microarray data sets.. Mammalian genome : official journal of the International Mammalian Genome Society. 17(9):941-9.
Mager J, Bartolomei MS.  2005.  Strategies for dissecting epigenetic mechanisms in the mouse.. Nature genetics. 37(11):1194-200.
Rivera-Pérez JA, Mager J, Magnuson T.  2003.  Dynamic morphogenetic events characterize the mouse visceral endoderm.. Developmental biology. 261(2):470-87.
Wang J, Mager J, Chen Y, Schneider E, Cross JC, Nagy A, Magnuson T.  2001.  Imprinted X inactivation maintained by a mouse Polycomb group gene.. Nature genetics. 28(4):371-5.
Name Phone Office
Cui , Wei Postdoctoral Research Associate 455
El Sebae , Gabriel 413-545-2339 455 ISB
Marcho , Chelsea Graduate Student 413-545-7372 455 ISB
Former Lab Personnel