My research goal is to gain a better understanding of how proteins that interact with DNA regulate RNA transcription, DNA replication and metazoan development. I mentor undergraduate and graduate students in my lab; we focus on the structure and function of the Nuclear Factor I (NFI) family of site-specific DNA binding proteins, and we are investigating their roles in development. Our work has been made possible by our development of loss-of-function mutations of the NFI genes in the mouse and C. elegans.
We are addressing four major questions in my laboratory and in collaboration with a number of talented collaborators: What is the structure of the NFI DNA-binding domain? How does NFI recognize and interact with DNA? Does NFI change the structure of DNA when it binds? What proteins interact with NFI to stimulate RNA transcription and/or DNA replication?
These research questions are explored in my lab through two major projects focused on the role of NFIB in lung development and the role of NFIX in brain development.
When NFIB is deleted from the germline of mice the animals die at birth because their lungs fail to mature normally. This provides a good model for the problems that occur with premature infants, whose lungs also fail to mature normally. We are using this model to determine how NFIB promotes lung maturation with the goal of being able to stimulate this process in premature infants.
In our NFIX knockout animals, the brains of the animals are actually larger than normal and contain large numbers of cells in an area known to be the site of postnatal neurogenesis. We have evidence that NFIX may regulate the proliferation and differentiation of neural stem cells, which produce new neurons throughout adult life. Our aim is to understand the specific target genes that NFIX regulates in the adult brain to control this process of neurogenesis.
Education and Training:
PhD, Physiology, Harvard University (1982)
MS, Biochemistry, Virginia Polytechnic Institute and State University (1977)
BS, Biochemistry, Virginia Polytechnic Institute and State University, With Honors (1975)
Employment:
Professor, 140 Farber Hall, University at Buffalo (2001-present)
Associate Professor, Biochemistry, Case Western Reserve University, School of Medicine (1992)
Assistant Professor, Medical Biophysics, Ontario Cancer Institute, University of Toronto, Canada (1985)
Research Expertise:
: Studies on NFI can be divided into two major themes: (1) biochemical analysis of NFI protein structure and function and (2) molecular genetic studies on NFI‘s role in cell growth, differentiation and development.
: (1) The DNA-binding domain of NFI differs from those found in other well characterized DNA-binding proteins. Four major questions being addressed in the laboratory are: What is the structure of the NFI DNA-binding domain? How does NFI recognize and interact with DNA? Does NFI change the structure of DNA when it binds? What proteins interact with NFI to stimulate RNA transcription and/or DNA replication?
: We have shown that the NFI-C protein represses the glucocorticoid-dependent expression of the MMTV promoter. This repression can be overcome by overexpression of the co-activator proteins CBP, p300 or SRC-1, suggesting a role of these co-activators in MMTV expression. Surprisingly, NFI-C doesn‘t repress progesterone stimulation of MMTV. We are currently working out the biochemical mechanism for this repression by NFI-C and the roles of co-activators, histone acetylase activity and chromatin remodeling activity in the process.
: (2) Using the mouse embryonic stem cell (ES cell) system and human leukemic cells, the role of NFI family members during cell differentiation is being studied. We showed previously that the forms of NFI present in ES and leukemic cells change during the differentiation of the cells in vitro. Currently we are asking the questions: By what mechanism does the form of NFI change during differentiation? How does the expression of different NFI family members affect pathways of differentiation? Is the expression of specific NFI family members required for the synthesis of specific classes of proteins in terminally differentiated cell types? What is the phenotype of mutant mice deficient in one or more NFI gene?
: The NFI-A deficient mouse we generated (Nfia-) has major neurological defects including agenesis of the corpus callosum and hydrocephalus. We‘re now studying the biochemical pathways leading to these developmental defects with the goal of determining how loss of a single transcription factor results in major neuroanatomical changes. We‘re focusing on whether loss of NFI-A causes changes in: 1) cell proliferation or death, 2) cell migration or differentiation, 3) axonal outgrowth, 4) axonal pathfinding, 5) glial cell differentiation and 6) patterns of neuronal or glial cell gene expression.
: While all vertebrates examined contain 4 highly conserved NFI genes (NFI-A, -B, -C and -X), the nematode Caenorhabditis elegans has only a single NFI gene (nfi-1). Unlike the case in vertebrates, where all 4 NFI genes are expressed in many tissues during both embryogenesis and throughout adult life, the C. elegans nfi-1 gene is expressed primarily during embryogenesis. In collaboration with Yuji Kohara we‘ve identified where nfi-1 mRNA is expressed in C. elegans and are assessing the phenotype of worms deficient in the nfi-1 gene product. By comparing the function of NFI in worms and mice, we are asking how NFI-dependent developmental pathways have been conserved through over 500M years of evolution.
: The goal of our laboratory is to gain a better understanding of how proteins that interact with DNA regulate RNA transcription and metazoan development. Our focus is on the structure and function of the Nuclear Factor I (NFI) family of site-specific DNA binding proteins. In vertebrates, NFI family members function in both the replication of viral DNA and the transcription of viral and cellular genes. We are currently analyzing the role of the NFI gene family in both vertebrate and C. elegans development.
Research Centers:
Center of Excellence in Bioinformatics and Life Sciences
UB 2020 Strategic Strengths:
Molecular Recognition in Biological Systems and Bioinformatics
Health and Wellness Across the Lifespan
Grants and Sponsored Research:
August 2011–July 2015 WNYSTEM, Western New York Stem Cell Culture and Analysis Center NYSTEM Role: Principal Investigator $3,564,599
September 2010–August 2013 Role of Nfix in Neural Stem Cells and glioblastoma NYSTEM Role: Co-Investigator $1,061,683
March 2007–February 2013 Role of NFI genes in mouse lung development NIH Role: Principal Investigator $1,981,250
–August 2005 Genes & Proteins Needed for NFI-regulated Transcription NIDDK Role: Principal Investigator $175,000
April 2002–March 2005 Novel Genes expressed during Kidney Development NIDDK Role: Principal Investigator $215,858
November 2001–March 2004 Novel Genes Expressed during Kidney Development NIDDK Role: Principal Investigator $259,593
Lu W, Quintero-Rivera F, Fan Y, Alkuraya FS, Donovan DJ, Xi Q, Turbe-Doan A, Li QG, Campbell CG, Shanske AL, Sherr EH, Ahmad A, Peters R, Rilliet B, Parvex P, Bassuk AG, Harris DJ, Ferguson H, Kelly C, Walsh CA, Gronostajski RM, Devriendt K, Higgins A, Ligon AH, Quade BJ, Morton CC, Gusella JF, Maas RL, Gronostajski R. NFIA haploinsufficiency is associated with a CNS malformation syndrome and urinary tract defects. PLoS Genet. 2007; 3(5).
Ling G, Hauer CR, Gronostajski RM, Pentecost BT, Ding X. Transcriptional Regulation of Rat CYP2A3 by Nuclear Factor 1: IDENTIFICATION OF A NOVEL NFI-A ISOFORM, AND EVIDENCE FOR TISSUE-SELECTIVE INTERACTION OF NFI WITH THE CYP2A3 PROMOTER IN VIVO.. J Biol Chem. 2004; 279(27).
Bachurski CJ, Yang GH, Currier TA, Gronostajski RM, Hong D. Nuclear factor I/thyroid transcription factor 1 interactions modulate surfactant protein C transcription.. Mol Cell Biol. 2003; 23(24).
Messam CA, Hou J, Gronostajski RM, Major EO. Lineage pathway of human brain progenitor cells identified by JC virus susceptibility.. Ann Neurol. 2003; 53(5).
Murtagh J, Martin F, Gronostajski RM. The Nuclear Factor I (NFI) gene family in mammary gland development and function.. J Mammary Gland Biol Neoplasia. 2003; 8(2).
Kido K, Bannert H, Gronostajski RM, Flügel RM. Bel1-mediated transactivation of the spumaretroviral internal promoter is repressed by nuclear factor I.. J Biol Chem. 2003; 278(14).
Pan L, Glenn ST, Jones CA, Gronostajski RM, Gross KW. Regulation of renin enhancer activity by nuclear factor I and Sp1/Sp3.. Biochim Biophys Acta. 2003; 1625(3).
Steele-Perkins G, Butz KG, Lyons GE, Zeichner-David M, Kim HJ, Cho MI, Gronostajski RM. Essential role for NFI-C/CTF transcription-replication factor in tooth root development.. Mol Cell Biol. 2003; 23(3).
Shu T, Butz KG, Plachez C, Gronostajski RM, Richards LJ. Abnormal development of forebrain midline glia and commissural projections in Nfia knock-out mice.. J Neurosci. 2003; 23(1).
Mukhopadhyay SS, Wyszomierski SL, Gronostajski RM, Rosen JM. Differential interactions of specific nuclear factor I isoforms with the glucocorticoid receptor and STAT5 in the cooperative regulation of WAP gene transcription.. Mol Cell Biol. 2001; 21(20).
Majumder S, Ghoshal K, Gronostajski RM, Jacob ST. Downregulation of constitutive and heavy metal-induced metallothionein-I expression by nuclear factor I.. Gene Expr. 2001; 9(4-5).
Majumder S, Ghoshal K, Gronostajski RM, Jacob ST. Downregulation of constitutive and heavy metal-induced metallothionein-I expression by nuclear factor I.. Gene Expr. 2001; 9(4-5).
Sinha S, Abraham S, Gronostajski RM, Campbell CE. Differential DNA binding and transcription modulation by three T-box proteins, T, TBX1 and TBX2.. Gene. 2000; 258(1-2).
Gronostajski RM. Roles of the NFI/CTF gene family in transcription and development.. Gene. 2000; 249(1-2).
Behrens M, Venkatraman G, Gronostajski RM, Reed RR, Margolis FL. NFI in the development of the olfactory neuroepithelium and the regulation of olfactory marker protein gene expression.. Eur J Neurosci. 2000; 12(4).
das Neves L, Duchala CS, Tolentino-Silva F, Haxhiu MA, Colmenares C, Macklin WB, Campbell CE, Butz KG, Gronostajski RM, Godinho F. Disruption of the murine nuclear factor I-A gene (Nfia) results in perinatal lethality, hydrocephalus, and agenesis of the corpus callosum.. Proc Natl Acad Sci U S A. 1999; 96(21).
Baumeister H, Gronostajski RM, Lyons GE, Margolis FL. Identification of NFI-binding sites and cloning of NFI-cDNAs suggest a regulatory role for NFI transcription factors in olfactory neuron gene expression.. Brain Res Mol Brain Res. 1999; 72(1).
Fletcher CF, Jenkins NA, Copeland NG, Chaudhry AZ, Gronostajski RM. Exon structure of the nuclear factor I DNA-binding domain from C. elegans to mammals.. Mamm Genome. 1999; 10(4).
Leahy P, Crawford DR, Grossman G, Gronostajski RM, Hanson RW. CREB binding protein coordinates the function of multiple transcription factors including nuclear factor I to regulate phosphoenolpyruvate carboxykinase (GTP) gene transcription.. J Biol Chem. 1999; 274(13).
Chaudhry AZ, Vitullo AD, Gronostajski RM. Nuclear factor I-mediated repression of the mouse mammary tumor virus promoter is abrogated by the coactivators p300/CBP and SRC-1.. J Biol Chem. 1999; 274(11).
Chaudhry AZ, Vitullo AD, Gronostajski RM. Nuclear factor I (NFI) isoforms differentially activate simple versus complex NFI-responsive promoters.. J Biol Chem. 1998; 273(29).
Crawford DR, Leahy P, Hu CY, Chaudhry A, Gronostajski R, Grossman G, Woods J, Hakimi P, Roesler WJ, Hanson RW. Nuclear factor I regulates expression of the gene for phosphoenolpyruvate carboxykinase (GTP).. J Biol Chem. 1998; 273(22).
Chaudhry AZ, Lyons GE, Gronostajski RM. Expression patterns of the four nuclear factor I genes during mouse embryogenesis indicate a potential role in development.. Dev Dyn. 1997; 208(3).
Kulkarni S, Gronostajski RM. Altered expression of the developmentally regulated NFI gene family during phorbol ester-induced differentiation of human leukemic cells.. Cell Growth Differ. 1996; 7(4).
Bandyopadhyay S, Gronostajski RM. Identification of a conserved oxidation-sensitive cysteine residue in the NFI family of DNA-binding proteins.. J Biol Chem. 1994; 269(47).
Novak A, Goyal N, Gronostajski RM. Four conserved cysteine residues are required for the DNA binding activity of nuclear factor I.. J Biol Chem. 1992; 267(18).
Knox JJ, Rebstein PJ, Manoukian A, Gronostajski RM. In vivo stimulation of a chimeric promoter by binding sites for nuclear factor I.. Mol Cell Biol. 1991; 11(6).
Goyal N, Knox J, Gronostajski RM. Analysis of multiple forms of nuclear factor I in human and murine cell lines.. Mol Cell Biol. 1990; 10(3).
Gronostajski RM, Knox J, Berry D, Miyamoto NG. Stimulation of transcription in vitro by binding sites for nuclear factor I.. Nucleic Acids Res. 1988; 16(5).
Gronostajski RM. Site-specific DNA binding of nuclear factor I: effect of the spacer region.. Nucleic Acids Res. 1987; 15(14).
Gronostajski RM. Analysis of nuclear factor I binding to DNA using degenerate oligonucleotides.. Nucleic Acids Res. 1986; 14(22).
Gronostajski RM, Sadowski PD. The FLP recombinase of the Saccharomyces cerevisiae 2 microns plasmid attaches covalently to DNA via a phosphotyrosyl linkage.. Mol Cell Biol. 1985; 5(11).
Gronostajski RM, Sadowski PD. The FLP protein of the 2-micron plasmid of yeast. Inter- and intramolecular reactions.. J Biol Chem. 1985; 260(22).
Gronostajski RM, Sadowski PD. Determination of DNA sequences essential for FLP-mediated recombination by a novel method.. J Biol Chem. 1985; 260(22).
Babineau D, Vetter D, Andrews BJ, Gronostajski RM, Proteau GA, Beatty LG, Sadowski PD. The FLP protein of the 2-micron plasmid of yeast. Purification of the protein from Escherichia coli cells expressing the cloned FLP gene.. J Biol Chem. 1985; 260(22).
Gronostajski RM, Adhya S, Nagata K, Guggenheimer RA, Hurwitz J. Site-specific DNA binding of nuclear factor I: analyses of cellular binding sites.. Mol Cell Biol. 1985; 5(5).
Gronostajski RM, Pardee AB, Goldberg AL. The ATP dependence of the degradation of short- and long-lived proteins in growing fibroblasts.. J Biol Chem. 1985; 260(6).
Gronostajski RM, Goldberg AL, Pardee AB. The role of increased proteolysis in the atrophy and arrest of proliferation in serum-deprived fibroblasts.. J Cell Physiol. 1984; 121(1).
Gronostajski RM, Field J, Hurwitz J. Purification of a primase activity associated with DNA polymerase alpha from HeLa cells.. J Biol Chem. 1984; 259(15).
Field J, Gronostajski RM, Hurwitz J. Properties of the adenovirus DNA polymerase.. J Biol Chem. 1984; 259(15).
Gronostajski RM, Nagata K, Hurwitz J. Isolation of human DNA sequences that bind to nuclear factor I, a host protein involved in adenovirus DNA replication.. Proc Natl Acad Sci U S A. 1984; 81(13).
Gronostajski RM, Pardee AB. Protein degradation in 3T3 cells and tumorigenic transformed 3T3 cells.. J Cell Physiol. 1984; 119(1).
Gronostajski RM, Goldberg AL, Pardee AB. Energy requirement for degradation of tumor-associated protein p53.. Mol Cell Biol. 1984; 4(3).
Friefeld BR, Lichy JH, Field J, Gronostajski RM, Guggenheimer RA, Krevolin MD, Nagata K, Hurwitz J, Horwitz MS. The in vitro replication of adenovirus DNA.. Curr Top Microbiol Immunol. 1984; 110.
Turner KJ, Gronostajski RM, Schmidt RR. Regulation of initial rate of induction of nicotinamide adenine dinucleotide phosphate-specific glutamate dehydrogenase during the cell cycle of synchronous Chlorella.. J Bacteriol. 1978; 134(3).
Gronostajski RM, Yeung AT, Schmidt RR. Purification and properties of the inducible nicotinamide adenine dinucleotide phosphate-specific glutamate dehydrogenase from Chlorella sorokiniana.. J Bacteriol. 1978; 134(2).
Israel DW, Gronostajski RM, Yeung AT, Schmidt RR. Regulation of accumulation and turnover of an inducible glutamate dehydrogenase in synchronous cultures of Chlorella.. J Bacteriol. 1977; 130(2).
Gronostajski R. Nuclear Factors. Encyc. Molec. Med.. 2002.
Richard Gronostajski. Nuclear Factors. Encyclopedia of Molecular Medicine. 2002; 4.
Richard Gronostajski. Nuclear Factor I. Encyclopedia of Molecular Medicine. 2002; 4.
Israel, D. W., Gronostajski R. M., Yeung, A. T., Schmidt, R. R.. Regulation of glutamate dehydrogenase induction and turnover during the cell cycle of the eukaryote Chlorella.. Cell Cycle Regulation. 1978.
Professional Memberships:
ASM (2003)
ASBMB (1990)
Presentations:
"Regenerative Medicine: A New Opportunity for Blood Center Diversification?" America's Blood Centers, America's Blood Centers (2012)
"WNYSTEM: Western New York Stem Cell Culture and Analysis Center" NYSTEM Annual Meeting, NYSTEM (2012)
"Multiple roles for Nuclear Factor I (NFI) transcription factors in the development of lung, brain, gut and other organ systems" Vanderbilt University, Vanderbilt University, Developmental Biology (2011)
"Multiple roles for Nuclear Factor I (NFI) transcription factors in the development of brain, lung and other organ systems" NIH (2011)
"Multiple roles for Nuclear Factor I (NFI) transcription factors in the development of brain, lung and other organ systems" Virginia Bioinformatics Institute, Virginia Tech (2011)
"Multiple roles for the Nuclear Factor I (NFI) transcription factor family in metazoan development" NIH, NID (2003)
Service Activities:
School of Medicine & Biomedical Sciences Faculty Council; Member (2003–2009)
Director Western New York Stem Cell Culture and Analysis Center; Director (2011)
Member Empire State Stem Cell Board (ESSCB); Member (2011)
Member Board of Directors UB Associates; Board of Directors (2009–2010)
Standing Committee for Facilities Planning and Budget; Chair (2008–2009)
Member Faculty Practice Management Plan Governing Board; Member (2008–2010)
Member Faculty Advisory Committee UB2020 Molecular Recognition in Biological Systems/Bioinformatics Strategic Strength; Member (2005)
Founder Developmental Genomics Focus of Excellence; Director (2004)
Member of Faculty Council 2003-2009; Member (2003–2009)
Member Search Committee Bioinformatics; Committee Member (2003–2006)
Chair of session in Frontiers of Bioinformatics 2003; Panel Member (2003)
Member IGPBS steering committee; Member (2003–2007)
Member Graduate Admissions committee; Member (2003–2007)
Member IRCAF review panel 2003; Ad Hoc Reviewer (2003)
Co-organizer of Biochemistry Annual Research Day; Organizing Committee Member (2003–2008)
Member MSTP Admissions/Steering Committee 2003-present; Member (2003)
Member IFR Committee 2001-present; Member (2001)
Clinical Specialties:
Clinical Offices:
Insurance Accepted:
Contact Information
Center of Excellence in Bioinformatics and Life Sciences 701 Ellicott St. Room 3-303 Buffalo, NY 14203 Phone: (716) 829-3471 Fax: (716) 849-6655 Email: rgron@buffalo.edu