Valerie Reinke, PhD
Research & Publications
Biography
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Research Summary
Germ cells are highly specialized cells with the unique responsibility of producing healthy offspring, thus ensuring the continuity of a species across generations. These cells guard their DNA very carefully to allow the production of sperm and eggs with the right number of chromosomes and no mutations. We wish to understand how germ cells protect their DNA, while turning different genes on and off at the right times to make functional sperm and eggs. To grasp the most important trends, we use global genomic technologies to investigate many genes simultaneously. We are studying germ cell regulation primarily using the model organism C. elegans, a nematode, because of the large number of germ cells it contains, and because of the many experimental advantages it offers. Because the genes in C. elegans are related to those in higher organisms, the results from our studies should help us to understand how germ cells function in humans as well.
Extensive Research Description
The genome carries all the information necessary for the development and function of an organism. This information is embedded at multiple levels - in the regulatory information of individual genes, in the partitioning of that sequence into chromatin domains, and in the spatial segregation of these domains into functionally distinct regions of the nucleus. This linear and spatial organization is essential for effective and precise deployment of genetic information, yet the underlying mechanisms that govern the three-dimensional architecture of the genome are just now being addressed, and fundamental questions remain unanswered: How does genome organization influence epigenetic information, and vice versa? How extensively does genome organization contribute to coordinated expression of functionally related genes? How does genome organization stabilize and instruct tissue-specific gene expression?
We address these questions in vivo with unprecedented cell specificity and comprehensiveness, utilizing innovative methods to investigate how genome structure and organization influences gene expression specifically in the C. elegans germ line. Specific projects are focused on:
Germline-specific expression of piRNA clusters. The C. elegans genome contains a remarkable genomic domain subject to tissue-specific expression. In C. elegans, thousands of individually transcribed loci encoding the piRNA class of small noncoding RNAs are clustered into two sharply demarcated regions on a single chromosome. Amazingly, these piRNAs exhibit synchronized expression in the germ line, despite being interspersed among hundreds of coding genes with diverse expression patterns. piRNA clustering is evolutionarily conserved, indicating that physical proximity is a key feature for coordinated expression, yet how germline-specific expression is implemented is a mystery. We have found that SNPC-4 preferentially binds across both piRNA clusters only in the germ line and promotes piRNA expression. SNPC-4 is a transcription factor known to stimulate the activity of both RNA polymerase II and III, and we have found that RNA polymerase III (pol III) also exhibits increased occupancy in piRNA clusters. Recently, pol III and core components of the pol III complex such as TFIIIC have been demonstrated to establish boundaries between genomic domains, and regulate gene expression within those domains. We are now determining the mechanisms by which SNPC-4 and the core RNA polymerase III machinery coordinately regulate this piRNA-rich genomic domain in a tissue-specific manner, within the native developmental context.
Regulation and function of germline transcription factors. In C. elegans, the germ line maintains a specific gene expression profile largely through the interaction between chromatin state and post-transcriptional RNA regulation. However, certain key transcription factors play a vital role in establishing and maintaining germline identity and separating the germline programs from the soma. In particular, the C. elegans version of the tumor suppressor complex Rb/E2F is vital to distinguishing germline and somatic identities. Gene expression and DNA binding profiles indicate that the complex acts as a repressor in the soma, and an activator in the germ line on completely separate gene targets. How this complex differentially regulates distinct target genes in specific tissues is poorly understood. We are now determining the tissue-specfici chromatin mechanisms by which this complex interacts with target genes. This analysis will have implications not only for germline development but also for human development and tumorigenesis. More broadly, we have defined additional novel regulatory factors that also appear to be expressed specifically in the germline and that have important roles in germline development. We are investigating how these factors are regulated as well as how they function, using a variety of genomic, genetic and biochemical assays.
Coauthors
Research Interests
Genetics; Germ Cells; Stem Cells; Developmental Biology; Caenorhabditis elegans; Genomics; Epigenomics
Public Health Interests
Genetics, Genomics, Epigenetics; Reproduction
Selected Publications
- The zinc-finger protein OEF-1 stabilizes histone modification patterns and promotes efficient splicing in the C. elegans germ lineMcManus CE, Mazzetto M, Wei G, Han M, Reinke V. The zinc-finger protein OEF-1 stabilizes histone modification patterns and promotes efficient splicing in the C. elegans germ line G3: Genes, Genomes, Genetics 2021, 11: jkab329-. PMID: 34519784, PMCID: PMC8664474, DOI: 10.1093/g3journal/jkab329.
- Isolated C. elegans germ nuclei exhibit distinct genomic profiles of histone modification and gene expressionHan M, Wei G, McManus CE, Hillier LW, Reinke V. Isolated C. elegans germ nuclei exhibit distinct genomic profiles of histone modification and gene expression BMC Genomics 2019, 20: 500. PMID: 31208332, PMCID: PMC6580472, DOI: 10.1186/s12864-019-5893-9.
- The modERN Resource: Genome-Wide Binding Profiles for Hundreds of Drosophila and Caenorhabditis elegans Transcription FactorsKudron MM, Victorsen A, Gevirtzman L, Hillier LW, Fisher WW, Vafeados D, Kirkey M, Hammonds AS, Gersch J, Ammouri H, Wall ML, Moran J, Steffen D, Szynkarek M, Seabrook-Sturgis S, Jameel N, Kadaba M, Patton J, Terrell R, Corson M, Durham TJ, Park S, Samanta S, Han M, Xu J, Yan KK, Celniker SE, White KP, Ma L, Gerstein M, Reinke V, Waterston R. The modERN Resource: Genome-Wide Binding Profiles for Hundreds of Drosophila and Caenorhabditis elegans Transcription Factors Genetics 2018, 208: genetics.300657.2017. PMID: 29284660, PMCID: PMC5844342, DOI: 10.1534/genetics.117.300657.
- The Germline-Specific Factor OEF-1 Facilitates Coordinated Progression Through Germ Cell Cevelopment in Caenorhabditis elegansMcManus CE, Reinke V. The Germline-Specific Factor OEF-1 Facilitates Coordinated Progression Through Germ Cell Cevelopment in Caenorhabditis elegans Genetics 2018, 208: genetics.1123.2017. PMID: 29167199, PMCID: PMC5788521, DOI: 10.1534/genetics.117.1123.
- A novel small molecule that disrupts a key event during the oocyte-to-embryo transition in C. elegansWeicksel SE, Mahadav A, Moyle M, Cipriani PG, Kudron M, Pincus Z, Bahmanyar S, Abriola L, Merkel J, Gutwein M, Fernandez AG, Piano F, Gunsalus KC, Reinke V. A novel small molecule that disrupts a key event during the oocyte-to-embryo transition in C. elegans Development 2016, 143: 3540-3548. PMID: 27510972, PMCID: PMC5087616, DOI: 10.1242/dev.140046.
- The C. elegans SNAPc Component SNPC-4 Coats piRNA Domains and Is Globally Required for piRNA AbundanceKasper DM, Wang G, Gardner KE, Johnstone TG, Reinke V. The C. elegans SNAPc Component SNPC-4 Coats piRNA Domains and Is Globally Required for piRNA Abundance Developmental Cell 2014, 31: 145-158. PMID: 25373775, PMCID: PMC4223638, DOI: 10.1016/j.devcel.2014.09.015.
- Regulatory analysis of the C. elegans genome with spatiotemporal resolutionAraya CL, Kawli T, Kundaje A, Jiang L, Wu B, Vafeados D, Terrell R, Weissdepp P, Gevirtzman L, Mace D, Niu W, Boyle AP, Xie D, Ma L, Murray JI, Reinke V, Waterston RH, Snyder M. Regulatory analysis of the C. elegans genome with spatiotemporal resolution Nature 2014, 512: 400-405. PMID: 25164749, PMCID: PMC4530805, DOI: 10.1038/nature13497.
- Comparative analysis of regulatory information and circuits across distant speciesBoyle AP, Araya CL, Brdlik C, Cayting P, Cheng C, Cheng Y, Gardner K, Hillier LW, Janette J, Jiang L, Kasper D, Kawli T, Kheradpour P, Kundaje A, Li JJ, Ma L, Niu W, Rehm EJ, Rozowsky J, Slattery M, Spokony R, Terrell R, Vafeados D, Wang D, Weisdepp P, Wu YC, Xie D, Yan KK, Feingold EA, Good PJ, Pazin MJ, Huang H, Bickel PJ, Brenner SE, Reinke V, Waterston RH, Gerstein M, White KP, Kellis M, Snyder M. Comparative analysis of regulatory information and circuits across distant species Nature 2014, 512: 453-456. PMID: 25164757, PMCID: PMC4336544, DOI: 10.1038/nature13668.
- Tissue-specific direct targets of Caenorhabditis elegans Rb/E2F dictate distinct somatic and germline programsKudron M, Niu W, Lu Z, Wang G, Gerstein M, Snyder M, Reinke V. Tissue-specific direct targets of Caenorhabditis elegans Rb/E2F dictate distinct somatic and germline programs Genome Biology 2013, 14: r5. PMID: 23347407, PMCID: PMC4053757, DOI: 10.1186/gb-2013-14-1-r5.
- C. elegans meg‐1 and meg‐2 differentially interact with nanos family members to either promote or inhibit germ cell proliferation and survivalKapelle WS, Reinke V. C. elegans meg‐1 and meg‐2 differentially interact with nanos family members to either promote or inhibit germ cell proliferation and survival Genesis 2011, 49: 380-391. PMID: 21305687, DOI: 10.1002/dvg.20726.
- The kinase VRK1 is required for normal meiotic progression in mammalian oogenesisSchober CS, Aydiner F, Booth CJ, Seli E, Reinke V. The kinase VRK1 is required for normal meiotic progression in mammalian oogenesis Cells And Development 2011, 128: 178-190. PMID: 21277975, DOI: 10.1016/j.mod.2011.01.004.
- Diverse transcription factor binding features revealed by genome-wide ChIP-seq in C. elegansNiu W, Lu ZJ, Zhong M, Sarov M, Murray JI, Brdlik CM, Janette J, Chen C, Alves P, Preston E, Slightham C, Jiang L, Hyman AA, Kim SK, Waterston RH, Gerstein M, Snyder M, Reinke V. Diverse transcription factor binding features revealed by genome-wide ChIP-seq in C. elegans Genome Research 2010, 21: 245-254. PMID: 21177963, PMCID: PMC3032928, DOI: 10.1101/gr.114587.110.
- Genome-wide analysis of germ cell proliferation in C . elegans identifies VRK-1 as a key regulator of CEP-1/p53Waters K, Yang AZ, Reinke V. Genome-wide analysis of germ cell proliferation in C . elegans identifies VRK-1 as a key regulator of CEP-1/p53 Developmental Biology 2010, 344: 1011-1025. PMID: 20599896, PMCID: PMC3375680, DOI: 10.1016/j.ydbio.2010.06.022.
- Genome-Wide Identification of Binding Sites Defines Distinct Functions for Caenorhabditis elegans PHA-4/FOXA in Development and Environmental ResponseZhong M, Niu W, Lu ZJ, Sarov M, Murray JI, Janette J, Raha D, Sheaffer KL, Lam HY, Preston E, Slightham C, Hillier LW, Brock T, Agarwal A, Auerbach R, Hyman AA, Gerstein M, Mango SE, Kim SK, Waterston RH, Reinke V, Snyder M. Genome-Wide Identification of Binding Sites Defines Distinct Functions for Caenorhabditis elegans PHA-4/FOXA in Development and Environmental Response PLOS Genetics 2010, 6: e1000848. PMID: 20174564, PMCID: PMC2824807, DOI: 10.1371/journal.pgen.1000848.
- DPL-1 (DP) acts in the germ line to coordinate ovulation and fertilization in C. elegansChi W, Reinke V. DPL-1 (DP) acts in the germ line to coordinate ovulation and fertilization in C. elegans Cells And Development 2009, 126: 406-416. PMID: 19368797, PMCID: PMC2680456, DOI: 10.1016/j.mod.2009.01.008.
- Massively parallel sequencing of the polyadenylated transcriptome of C. elegansHillier LW, Reinke V, Green P, Hirst M, Marra MA, Waterston RH. Massively parallel sequencing of the polyadenylated transcriptome of C. elegans Genome Research 2009, 19: 657-666. PMID: 19181841, PMCID: PMC2665784, DOI: 10.1101/gr.088112.108.
- C. elegans Nucleostemin Is Required for Larval Growth and Germline Stem Cell DivisionKudron MM, Reinke V. C. elegans Nucleostemin Is Required for Larval Growth and Germline Stem Cell Division PLOS Genetics 2008, 4: e1000181. PMID: 18725931, PMCID: PMC2515194, DOI: 10.1371/journal.pgen.1000181.
- A C. elegans Piwi, PRG-1, Regulates 21U-RNAs during SpermatogenesisWang G, Reinke V. A C. elegans Piwi, PRG-1, Regulates 21U-RNAs during Spermatogenesis Current Biology 2008, 18: 861-867. PMID: 18501605, PMCID: PMC2494713, DOI: 10.1016/j.cub.2008.05.009.
- MEG-1 and MEG-2 Are Embryo-Specific P-Granule Components Required for Germline Development in Caenorhabditis elegansLeacock SW, Reinke V. MEG-1 and MEG-2 Are Embryo-Specific P-Granule Components Required for Germline Development in Caenorhabditis elegans Genetics 2008, 178: 295-306. PMID: 18202375, PMCID: PMC2206079, DOI: 10.1534/genetics.107.080218.
- Regulation of developmental rate and germ cell proliferation in Caenorhabditis elegans by the p53 gene networkDerry W, Bierings R, van Iersel M, Satkunendran T, Reinke V, Rothman J. Regulation of developmental rate and germ cell proliferation in Caenorhabditis elegans by the p53 gene network Cell Death & Differentiation 2006, 14: 662-670. PMID: 17186023, DOI: 10.1038/sj.cdd.4402075.
- Promotion of oogenesis and embryogenesis in the C. elegans gonad by EFL-1/DPL-1 (E2F) does not require LIN-35 (pRB)Chi W, Reinke V. Promotion of oogenesis and embryogenesis in the C. elegans gonad by EFL-1/DPL-1 (E2F) does not require LIN-35 (pRB) Development 2006, 133: 3147-3157. PMID: 16854972, DOI: 10.1242/dev.02490.
- p38 MAPK Regulates Expression of Immune Response Genes and Contributes to Longevity in C. elegansTroemel E, Chu S, Reinke V, Lee S, Ausubel F, Kim D. p38 MAPK Regulates Expression of Immune Response Genes and Contributes to Longevity in C. elegans PLOS Genetics 2005, preprint: e183. DOI: 10.1371/journal.pgen.0020183.eor.
- A Targeted RNAi Screen for Genes Involved in Chromosome Morphogenesis and Nuclear Organization in the Caenorhabditis elegans GermlineColaiácovo M, Stanfield G, Reddy K, Reinke V, Kim S, Villeneuve A. A Targeted RNAi Screen for Genes Involved in Chromosome Morphogenesis and Nuclear Organization in the Caenorhabditis elegans Germline Genetics 2002, 162: 113-128. PMID: 12242227, PMCID: PMC1462232, DOI: 10.1093/genetics/162.1.113.
- X-chromosome silencing in the germline of C. elegans.Kelly WG, Schaner CE, Dernburg AF, Lee MH, Kim SK, Villeneuve AM, Reinke V. X-chromosome silencing in the germline of C. elegans. Development 2002, 129: 479-92. PMID: 11807039, PMCID: PMC4066729, DOI: 10.1242/dev.129.2.479.
- Genome-wide analysis of developmental and sex-regulated gene expression profiles in Caenorhabditis elegansJiang M, Ryu J, Kiraly M, Duke K, Reinke V, Kim S. Genome-wide analysis of developmental and sex-regulated gene expression profiles in Caenorhabditis elegans Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 98: 218-223. PMID: 11134517, PMCID: PMC14571, DOI: 10.1073/pnas.98.1.218.
- A Global Profile of Germline Gene Expression in C. elegansReinke V, Smith H, Nance J, Wang J, Van Doren C, Begley R, Jones S, Davis E, Scherer S, Ward S, Kim S. A Global Profile of Germline Gene Expression in C. elegans Molecular Cell 2000, 6: 605-616. PMID: 11030340, DOI: 10.1016/s1097-2765(00)00059-9.