Miguel Angel Brieño-Enríquez , M.D., Ph.D.

  • Assistant Professor
  • Department of OBGYN and Reproductive Services, MWRI

Education & Training

  • M.D. Universidad Autonoma de San Luis Potosi, Mexico, Medicine-2003
  • MSc. Universitat Autonoma de Barcelona, Spain, Cell Biology- 2007
  • Ph.D. Universitat Autonoma de Barcelona, Spain, Cell Biology- 2011
  • PostDoc, Centro de Investigaciones Biologicas CSIC, Spain- Cell Biology-2013
  • PostDoc, Cornell University, 2018- Cell Biology

Research Interest Summary

Research in the Brieño-Enríquez lab focuses in the regulation of germ cell development and reproductive aging in human, mouse and the naked mole rat, more specifically, the fundamental mechanisms that are required to produce viable germ cells as well as i

Research Categories

Research Interests

Protection of ovarian reserve and reproductive aging in mammals

In mammals, it is generally thought that the total number of oocytes and follicles in adult ovaries is established during pre- and perinatal life. However, the number of oocytes at birth can be modulated by any number of endogenous and exogenous factors. During the last two decades, several groups have been investigating and reporting on the presence of postnatal oogenesis in mammals; however, the results of these studies have been heavily debated in the field. Because naked mole-rats (NMRs, Heterocephalus glaber) reportedly demonstrate no decline in fertility and fecundity into their third decade of life, we have recently begun to study NMR ovarian development to elucidate the means by which they accomplish this remarkable feat. These include the possibilities that NMRs generate new oocytes during the postnatal life and/or that they establish a very large ovarian reserve during pre- and perinatal life. Collectively, our results show, for first time, that ovarian germ cell development is highly asynchronous in NMRs, which is a developmental characteristic that NMRs share with humans. Because NMRs and humans also both have long reproductive lifespans that comprise decades, the NMR is an excellent laboratory model system for studying the processes that lead to variations in the size of the ovarian reserve and that modulate the age of onset of reproductive senescence.

Regulation of cohesin removal mediated by NEK1 kinase

The cohesin complex is essential for maintaining sister chromatid cohesion and correcting chromosome segregation in both mitosis and meiosis. In mitosis, cohesin removal is orchestrated in two steps: (1) the prophase pathway and (2) cleavage by separase. The prophase pathway depends on the proper activity of wings apart-like (WAPL). WAPL action is dependent on its interaction with regulator of cohesion maintenance, homolog B (PDS5B) and phosphorylation of sororin. While the regulation of the prophase pathway and mechanisms that control WAPL activity have been extensively studied in mitosis, these processes have not been characterized extensively in meiosis. The serine/threonine and tyrosine dual-specificity NIMA-like kinase-1, NEK1, is highly expressed in testis and is required for accurate cohesin removal at the first meiotic division via mechanisms that were hitherto unknown. My studies demonstrate the regulative role of NEK1 during the meiotic prophase pathway. NEK1 phosphorylates the cohesins SMC3 and REC8 and also regulates the stability and/or action of WAPL. Analysis using mass spectrometry reveals that Nek1 mutants show abnormal phosphorylation of serine 549 of RAD21, serine 1067 on SMC3, and serine 226 on WAPL. Using immunoprecipitation followed by mass spectrometry, I revealed that the protein phosphatase PP1γ interacts with both NEK1 and WAPL. Using PP1γ inhibitors and PP1γ mutant mice, I confirmed that the lack of PP1γ phosphorylation or protein induces a phenotype that mimics the Nek1 mutant. These results also show that NEK1 interacts indirectly with WAPL binding partner PDS5B. Taken together, my data demonstrate that NEK1 is essential for the prophase pathway regulating cohesin phosphorylation and maintaining unphosphorylated WAPL through a mechanism mediated by PP1γ.

Transgenerational epigenetic effects, PGCs, and non-coding RNAs

In mammals, Primordial Germ Cells (PGCs) give rise to the germ cell pool during fetal development. I investigated the question of whether prenatal exposure to environmental toxicants such as endocrine disruptors may alter PGC differentiation and development of the male germline and may induce transgenerational epigenetic disorders. The anti-androgenic compound vinclozolin represents a strong example of a molecule that causes transgenerational effects on germ cells through a mechanism mediated by changes in methylation.  My studies in this area showed for very first time that prenatal exposure to vinclozolin in mice induced changes in microRNAs (miRNAs) and their targets across three successive generations. This transgenerational effect was characterized by a reduction in the number of PGCs, increased apoptosis, and decreased fertility rate in adult males across generations. The number and quality of PGCs during embryogenesis depends on a series of factors, such as Blimp1, Lin28, and the miRNA Let7, and all of them are crucial regulators of PGC differentiation. My results showed that exposure to vinclozolin deregulated specific miRNAs in PGCs, such as miR-23b and miR-21, inducing disequilibrium in the Lin28/let-7/Blimp1 pathway in three successive generations of males. Taken together, my data showed that embryonic exposure to environmental endocrine disruptors induces transgenerational epigenetic deregulation of expression of miRNAs affecting key regulatory pathways of germ cell differentiation without changes in methylation.

Representative Publications

Miguel A. Brieño-Enríquez, Stefannie L. Moak, Anyul Abud-Flores, Paula Elaine Cohen. Characterization of Telomeric Repeat-Containing RNA (TERRA) localization and protein interactions in Primordial Germ Cells of the mouse. Biol Reprod. 2019 Apr 1;100(4):950-962. doi: 10.1093/biolre/ioy243. PubMed PMID: 30423030; PubMed Central PMCID: PMC6483056.

Daniel Fernández-Pérez D, Miguel A. Brieño-Enríquez, Javier Isoler-Alcaraz, Eduardo Larriba, Jesus del Mazo. MicroRNA dynamics at the onset of primordial germ and somatic cell sex differentiation during mouse embryonic gonad development. RNA. 2018 Mar;24(3):287-303. doi:10.1261/rna.062869.11

Miguel A. Brieño-Enríquez, Eduardo Larriba, Jesús del Mazo. (2016) Endocrine disrupters, microRNAs, and primordial germ cells: a dangerous cocktail. Fertility and Sterility 106:871-879.

Miguel A. Brieño-Enríquez, J. Garcia-Lopez, D. B. Cardenas, S. Guibert, E. Cleroux, L. Ded, D. Hourcade Jde, J. Peknicova, M. Weber and J. Del Mazo (2015). "Exposure to endocrine disruptor induces transgenerational epigenetic deregulation of microRNAs in primordial germ cells." PLoS One 10(4): e0124296. PMCID:4405367

Miguel A. Brieño-Enriquez, Mariela Faykoo-Martinez, Meagan Goben, Jennifer K. Grenier, Ashley McGrath, Alexandra M. Prado, Jacob Sinopoli, Kate Wagner, Paula E. Cohen, Diana J. Laird, Melissa M. Holmes, Ned J. Place. Postnatal oogenesis in the naked mole-rat. Submitted

Ned J Place, Alexandra M Prado, Mariela Faykoo-Martinez, Miguel Angel Brieño-Enriquez, David F Albertini, Melissa M Holmes. Germ cell nests in adult ovaries and an unusually large ovarian reserve in the naked mole-rat. PMID: 33151901 DOI: 10.1530/REP-20-0304

R. Buffenstein, V. Amarosa, B. Andziak, S. Avdieiev, J. Azpurua, A.J. Barker, N.C. Bennett, Miguel Angel Brieño-Enríquez,  G.N. Bronner, C. Coen, M.A. Delaney, C.M. Dengler-Crish, Y. Edrey, C.G. Faulkes, D. Frankel, G. Friedlander, P.A. Gibney, V. Gorbunova, R. Heffner, C. Hine, M.M. Holmes, J.U.M. Jarvis, Y. Kawamura, C. Kenyon, W.T. Khaled, T. Kikusui, J. Kissil, S. Lagestee, J. Larson, A. Lauer, L.A. Lavrenchenko, A. Lee, J.B. Levitt, G.R. Lewin, K.N. Lewis, M.J. Mason, D. McCloskey, M.

McMahon, K. Miura, K. Mogi,  V. Narayan, T.P. O’Connor, Y. Oiwa, K. Okanoya, T.J. Park, N.J. Place, K. Podshivalova, M.E. Pamenter, S.J. Pyott,  J. Reznick,  J.G. Ruby, A.B. Salmon, J. Santos-Sacchi, D. Sarko, A. Seluanov, A. Shepard, M. Smith, K.B. Storey, X. Tian, E.N. Vice, M. Viltard, A. Watarai, E. Wywial, E.D. Zemlemerova, M. Zions,  E. St. John Smith. The naked truth: busting the myths of naked mole-rat biology. Biol Rev Camb Philos Soc. 2021 Sep 3. doi: 10.1111/brv.12791. Online ahead of print. PMID: 3447689.

Miguel A. Brieño-Enríquez, Stefannie L Moak, J Kim Holloway, Paula Elaine Cohen. (2017) NIMA-related kinase 1 (NEK1) regulates the localization and phosphorylation of α-Adducin (ADD1) and Myosin X (MYO10) during meiosis. PLoS ONE 12(10): e0185780.

Miguel A. Brieño-Enríquez, Stefannie L. Moak, Melissa Toledo, Joshua J. Filter, Stephen Gray, José L. Barbero, Paula E. Cohen and J. Kim Holloway. (2016) Cohesin removal along the chromosome arms during the first meiotic division depends on a NEK1-PP1γ-WAPL axis in the mouse. Cell Reports 17:977–986.

Rachel Marie Beverley, Meredith Snook, Miguel A. Brieño-Enriquez.  Meiotic cohesin and variants associated with human reproductive aging and disease. Front. Cell Dev. Biol., 02 August 2021  https://doi.org/10.3389/fcell.2021.710033. PMCID: PMC8139203.

Full List of Publications