Austin J. Cooney, Ph.D.
Department of Molecular and Cellular Biology
Ph.D.: National University of Ireland, Galway, Ireland
Postdoctoral training: Baylor College of Medicine, Houston
Nuclear receptor regulation of embryonic stem cell function
Human ES cells have the potential to be used in regenerative therapies to treat many diseases by replacing damaged tissue. A long-term hope is that re-programming of patient derived cells to generate ES cells will permit the generation of isogenic therapies. The rate-limiting step in re-programming by somatic cell nuclear transfer is the reactivation of the Oct4 gene. Understanding the maintenance and silencing of pluripotency gene expression will help in understanding the reverse process of re-programming. One of my long-term research goals is to understand how gene expression is regulated in ES cells to maintain self-renewal and pluripotence; I am also interested in the flip side of this question, how is pluripotency genes silenced during ES cell differentiation. To this field I bring some unique expertise from the world of nuclear receptors.
My second research interest is to understand how nuclear receptors regulate gene expression to affect alterations in phenotype and physiology in response to hormones. Nuclear receptors constitute a discrete gene family encoding ligand-activated transcription factors, which includes orphan receptors whose ligands and functions are unknown. Orphan receptors, which constitute half of the 48 gene family, are part of the druggable genome and represent a current and future growth area in biomedical research. Understanding the novel physiological roles and mechanisms of action of orphan receptors will ultimately translate into understanding human disease and ultimately developing novel treatments and therapies.
Our in vivo model system is the mouse. We employ various knock-out, knock-in, and transgenic strategies to study the roles of orphan receptors in regulating gene expression and differentiation in early embryonic development. Our in vitro model system for dissecting the transcriptional role of nuclear receptors are embryonic stem cells. Our major system for mechanistic studies are mouse ES cells and we translate our findings to human ES cells.
Oct4 and Nanog expression in a mouse
embryonic stem cell embryoid body
detected by immunofluorescence.
Baylor College of Medicine
One Baylor Plaza,
Houston, TX 77030
- Gu P, Xu X, Le Menuet D, Chung AC and Cooney AJ. (2011). Differential Recruitment of MBDs and Dnmts by the Orphan Receptor GCNF Initiates the Repression and Silencing of Oct4. Stem Cells. 29: 1041-1051. PMID: 2160807.
- Wagner RT, Xu X, Yi F, Merrill BJ and Cooney, AJ. (2010). Canonical Wnt/b-Catenin Regulation of Liver Receptor Homolog-1 Mediates Pluripotency Gene Expression. Stem Cells 10:1794-804 PMID: 20734354.
- Gu P, Reid J, Gao X, Shaw C, Tran P L, Zhou X, Drabek R, Havlak P, Steffen DL, Garbino A, Hoang D, Weiss MK, Naghavi AO, El-daye J, Wheeler D, Legge G, Yuan Y, Gibbs RA, Miller J, Cooney AJ and Gunaratne PH. (2008).Novel MicroRNA Candidates and MiRNA-mRNA Pairs in Embryonic Stem (ES) Cells. Plos One 3(7): e2548. doi:10.1371/journal.pone.0002548 PMID: 18648548
- Chung AC-K, Xu X, Neiderreither K, Cooney AJ (2006). Orphan Nuclear Receptor GCNF is Required for the Establishment of Forebrain and isthmic organizer. Developmental Biol. 293: 13-24. PMID: 16530751.
- Gu P, LeMenuet D, Chung AC-K, Mancini M, Wheeler D and Cooney AJ. (2005). Orphan nuclear receptor GCNF is required for the repression of pluripotency genes during ES cell differentiation. Mol. Cell. Biol. 25:8507-8519. PMID: 16166633.
- Gu P, Goodwin B, Chung AC-K, Xu X, Wheeler D, Price RR, Galardi C, Peng L, Latour AM, Koller BH, Gossen J, Kliewer SA and Cooney AJ. (2005). Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development. Molecular and Cellular Biology 25: 3492-3505 PMID: 15831456.
- Hummelke GC and Cooney AJ. (2004). Reciprocal Regulation of the Mouse Protamine Genes by Germ Cell Nuclear Factor and CREMt. Mol. Repro. and Dev. 68: 394-407. PMID: 15236322.
- Lan Z-J, Gu P, Xu X, Jackson K, DeMayo FJ, O’Malley BW and Cooney, AJ. (2003). GCNF-dependent repression of BMP-15 and GDF-9 expression mediates gamete regulation of female fertility. EMBO Journal 22(16):4070-4081, 2003. PMID: 12912906.
- Lan, Z-J, Chung AC-K, Xu X, DeMayo FJ and Cooney AJ. (2002). The embryonic function of germ cell nuclear factor is dependent on the DNA binding domain., J. Biol Chem, 277(52):50660-50667. PMID: 12381721.
- Fuhrmann G, Chung AC-K, Jackson KJ, Hummelke G, Baniahmad A, Sutter J, Sylvester I, Schöler HR and Cooney, AJ. (2001) Mouse Germline Restriction of Oct4 Expression by Germ Cell Nuclear Factor. Developmental Cell 1:377-387 . Review: Donovan, P.J. High Oct-ane fuel powers the stem cell. Nature Genetics 29:246-247 (2001). PMID: 11702949.