Montserrat C Anguera
Assistant Professor, Department of Animal BiologyContact Information
Department of Animal Biology
School of Veterinary Medicine
3800 Spruce St., Room 390EB
Philadelphia, PA 19147
B.A (Environmental Chemistry) University of California, San Diego, 1998
Ph.D (Biochemistry, Molecular and Cellular Biology) Cornell University, 2004
PublicationsSearch PubMed for Articles
Description of Research Expertise
Roles of long noncoding RNAs during early development and how their misregulation results in disease
Long Noncoding RNAs, Human Pluripotent Stem Cells, Epigenetics, X-Chromosome Inactivation
Long noncoding RNAs (lncRNAs) are young and exciting players in the field of epigenetic gene regulation, where heritable changes in expression are independent of DNA sequence. One of the remarkable findings of the Human Genome Sequencing Project was that just 2% of the genome is protein coding, yet 70-90% of the genome is transcribed. Next-Generation Sequencing experiments have sparked investigation into this ‘dark matter’ of the genome, and recent estimates suggest that the lncRNA family contains 10,000- 200,000 members. These lncRNAs exhibit cell-type and tissue specific expression, yet functional information is only available for small handful of these lncRNAs.
X-Chromosome Inactivation (XCI) is a hallmark example of epigenetic regulation completely dependent on lncRNAs. Mammals have evolved chromosome-wide silencing mechanism relying on X-linked lncRNAs to equalize X-gene dosage between genders. The master regulator of XCI is the lncRNA XIST, which is upregulated from the inactivate X-chromosome during differentiation and forms a cytologically visible RNA ‘cloud’. XIST RNA is well conserved, yet mechanisms of XCI differ between mouse and human, and the epigenetic instability of human pluripotent stem cells frequently silences XIST. We recently discovered that XIST-negative female hiPSCs have cancer-related phenotypes, compromising their use as biological models and in clinical settings.
Our lab is interested in the function and molecular mechanisms of lncRNAs and how their mis-regulation contributes to disease. We are investigating these mechanisms using human and mouse pluripotent stem cells and mouse models, using molecular, genetic, and biochemical approaches.
1. Causes and Consequences of Altered Dosage Compensation
Regenerative medicine holds great promise for treating genetic and trauma-induced disease. Pluripotent stem cells (PSCs) have the potential to differentiate into all cell types, underscoring their importance for therapeutic applications. However, human PSCs (hPSCs) are susceptible to genetic and epigenetic instability, which questions their utility and safety in clinical settings. Female hPSCs display remarkable variability of X-Chromosome Inactivation, and frequently lack XIST RNA expression. We discovered that XIST-negative female hiPSCs have cancer-related phenotypes (increased cell growth rates, poor differentiation potential, and altered gene expression for coding and long noncoding RNAs), posing a health risk for female patients. We are using these cells to determine the mechanisms that initiate undesirable epigenetic change in order to identify pathways that can be targeted to prevent epigenetic instability.
2. Mechanisms of an X-linked lncRNA (Tsx) in cell proliferation and differentiation
The Tsx gene was originally described as a protein-coding gene predominantly expressed in the testes, yet lacks protein domain homology and proteomic detection. We discovered that Tsx is robustly transcribed from a silent X-chromosome, similar to Xist RNA, escaping chromosome-wide silencing during male meiosis. We used in vivo and in vitro experiments to demonstrate that Tsx is not protein-coding, but actually a novel lncRNA. Tsx RNA is present in a variety of adult tissues, notably the brain and reproductive systems. There are different Tsx RNA isoforms, many lacking open reading frames, which are expressed in cell-specific contexts. We found that Tsx null mESCs exhibit severe growth inhibition, poor differentiation, and mis-regulated expression of ncRNAs important for XCI. Our lab is interested in investigating how Tsx deletion results in these phenotypes and identifying protein binding partners required for Tsx function.
Anguera Montserrat C, Sadreyev Ruslan, Zhang Zhaoqing, Szanto Attila, Payer Bernhard, Sheridan Steven D, Kwok Showming, Haggarty Stephen J, Sur Mriganka, Alvarez Jason, Gimelbrant Alexander, Mitalipova Maisam, Kirby James E, Lee Jeannie T: Molecular signatures of human induced pluripotent stem cells highlight sex differences and cancer genes. Cell stem cell 11(1): 75-90, Jul 2012.
Anguera Montserrat C, Ma Weiyuan, Clift Danielle, Namekawa Satoshi, Kelleher Raymond J, Lee Jeannie T: Tsx produces a long noncoding RNA and has general functions in the germline, stem cells, and brain. PLoS genetics 7(9): e1002248, Sep 2011.
Kim Daniel H, Jeon Yesu, Anguera Montserrat C, Lee Jeannie T: X-chromosome epigenetic reprogramming in pluripotent stem cells via noncoding genes. Seminars in cell & developmental biology 22(4): 336-42, Jun 2011.
Field Martha S, Anguera Montserrat C, Page Rodney, Stover Patrick J: 5,10-Methenyltetrahydrofolate synthetase activity is increased in tumors and modifies the efficacy of antipurine LY309887. Archives of biochemistry and biophysics 481(2): 145-50, Jan 2009.
Anguera Montserrat C, Liu Matthew, Avruch Joseph, Lee Jeannie T: Characterization of two Mst1-deficient mouse models. Developmental dynamics : an official publication of the American Association of Anatomists 237(11): 3424-34, Nov 2008.
Anguera Montserrat C, Stover Patrick J: Methenyltetrahydrofolate synthetase is a high-affinity catecholamine-binding protein. Archives of biochemistry and biophysics 455(2): 175-87, Nov 2006.
Anguera Montserrat C, Field Martha S, Perry Cheryll, Ghandour Haifa, Chiang En-Pei, Selhub Jacob, Shane Barry, Stover Patrick J: Regulation of folate-mediated one-carbon metabolism by 10-formyltetrahydrofolate dehydrogenase. The Journal of biological chemistry 281(27): 18335-42, Jul 2006.
Anguera M C, Sun B K, Xu N, Lee J T: X-chromosome kiss and tell: how the Xs go their separate ways. Cold Spring Harbor symposia on quantitative biology 71: 429-37, 2006.
Anguera Montserrat C, Liu Xiaowen, Stover Patrick J: Cloning, expression, and purification of 5,10-methenyltetrahydrofolate synthetase from Mus musculus. Protein expression and purification 35(2): 276-83, Jun 2004.
Anguera Montserrat C, Suh Jae Rin, Ghandour Haifa, Nasrallah Ilya M, Selhub Jacob, Stover Patrick J: Methenyltetrahydrofolate synthetase regulates folate turnover and accumulation. The Journal of biological chemistry 278(32): 29856-62, Aug 2003.