A longstanding interest of the Chess lab is the study of unusual mechanisms involved in regulating gene expression. Recently we have been developing approaches to allow the study of epigenetic regulation at the scale of the entire human genome. Understanding of epigenetic mechanisms is essential to understanding normal development and disease.
Are there yet uncovered mechanisms impacting gene regulation which can be discovered through genome-scale approaches?
What gives individual cells their identities?
How unique are individual cells?
These questions and others have been approached in studies of various species including Humans, mice and the fruit fly, Drosophila melanogaster.
Andrew Chess, MD
Professor, Genetics and Genomic Sciences
Professor, Cell, Developmental & Regenerative Biology
Office: Annenberg 25-62B
DNA methylation stands out amongst epigenetic marks in that it is a covalent modification of the DNA molecule itself (albeit a modification that doesn’t change the DNA sequence). For DNA methylation (specifically methylation of cytosines within CpG dinucleotides) there is a known mechanism for replicating the mark. The DNA methyltransferase I encodes a protein which recognizes hemi-methylated DNA (arising from the replication of a double-stranded methylated DNA molecule) and methylates the other strand. Genome-scale analyses of DNA methylation have led to the first demonstration of methylation of the gene body (the entire transcribed region) of mammalian genes. This work also showed more methylation on the active X than the inactive X in female cells (Hellman and Chess, 2007). These observations resulted from our decision to consider all types of CpGs rather than earlier studies that focused on CpG islands. Gene body methylation, which is present in plant genomes as well as animal genomes, adds another layer of complexity to the role of DNA methylation in regulation of the genome.
Polymorphism in DNA sequence is well known, but until recently the potential for DNA methylation polymorphism was not explored. We and others have found evidence for such DNA methylation polymorphism. Our genome-scale analyses have revealed an interesting interplay between DNA sequence polymorphism and DNA methylation polymorphism (Hellman and Chess, 2010).
Random monoallelic expression
Monoallelic expression represents a good model system for studying epigenetics because it requires the differential treatment of two alleles (which are sometimes identical in sequence). Monoallelic expression with random choice between the maternal and paternal alleles defines an unusual class of genes comprising X-inactivated genes and a few autosomal gene-families. Using a genome-wide approach, a few years ago we assessed allele-specific transcription of ~4,000 human genes in clonal cell lines and found that over 300 were subject to random monoallelic expression (Gimelbrant et al., 2007). For a majority of monoallelic genes, they observed some clonal lines displaying biallelic expression. Clonal cell lines reflect an independent choice to express the maternal, the paternal, or both alleles for each of these genes. This can lead to differences in expressed protein sequence, and to differences in levels of gene expression.
Widespread monoallelic expression suggests a mechanism that generates diversity in individual human cells and their clonal descendants. We have extended these observations to the mouse genome (in preparation, 2011).
Some other highlights
- Discovery of allelic exclusion of mouse odorant receptor genes (Chess et al., 1996).
- Identification of the odorant receptor gene family in Drosophila, along with the demonstration that different olfactory neurons express different receptors and converge in their projections to the antennal lobe creating a spatial representation of olfactory space (Gao and Chess, 1999; Gao et al., 2000).
- Elucidation of a role for asynchronous replication in immunoglobulin gene allelic exclusion (Mostoslavsky et al., 2001).
- Demonstration of chromosome-level coordination of replication timing in mouse and human cells (Singh et al., 2003; Ensminger and Chess, 2004).
- Cloning of a mouse from an olfactory neuron (Eggan et al., 2004).
- Insights into the evolution of the odorant receptor gene family in humans (Gimelbrant et al., 2004).
- Uncovering a role for alternative splicing in the specification of unique identity of neurons (Neves et al., 2004; Zhan et al., 2004).
- Discovery of a non-coding RNAs associated with nuclear structures, and the demonstration that one of them, NEAT1, plays a structural role in the nuclear parapspeckle (Hutchinson et al., 2007; Clemson et al., 2009).
Adegbola A, Musante L, Callewaert B, Maciel P, Hu H, Isidor B, Picker-Minh S, Le Caignec C, Delle Chiaie B, Vanakker O, Menten B, Dheedene A, Bockaert N, Roelens F, Decaestecker K, Silva J, Soares G, Lopes F, Najmabadi H, Kahrizi K, Cox GF, Angus SP, Staropoli JF, Fischer U, Suckow V, Bartsch O, Chess A, Ropers HH, Wienker TF, Hubner C, Kaindl AM, Kalscheuer VM. Redefining the MED13L syndrome. Eur J Hum Genet 2015 Oct;23(10):1308-17.
Adegbola AA, Cox GF, Bradshaw EM, Hafler DA, Gimelbrant A, Chess A. Monoallelic expression of the human FOXP2 speech gene. Proc Natl Acad Sci U S A 2015 Jun 2;112(22):6848-54.
Beaulaurier J, Zhang XS, Zhu S, Sebra R, Rosenbluh C, Deikus G, Shen N, Munera D, Waldor MK, Chess A, Blaser MJ, Schadt EE, Fang G. Single molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes. Nat Commun 2015;6:7438.
Hutchinson JN, Fagerness J, Kirby A, Reynolds R, Zak A, Gimelbrant A, Plenge R, Daly M, Chess A, Seddon JM. (Epi)Genetic analyses of age-related macular degeneration: case-control and discordant twin studies. Hum Hered 2014;78(2):59-72.
Hutchinson JN, Raj T, Fagerness J, Stahl E, Viloria FT, Gimelbrant A, Seddon J, Daly M, Chess A, Plenge R. Allele-specific methylation occurs at genetic variants associated with complex disease. PLoS One 2014;9(6):e98464.
Schadt EE, Banerjee O, Fang G, Feng Z, Wong WH, Zhang X, Kislyuk A, Clark TA, Luong K, Keren-Paz A, Chess A, Kumar V, Chen-Plotkin A, Sondheimer N, Korlach J, Kasarskis A. Modeling kinetic rate variation in third generation DNA sequencing data to detect putative modifications to DNA bases. Genome Res 2013 Jan;23(1):129-41.
Chess A. Random and non-random monoallelic expression. Neuropsychopharmacology 2013 Jan;38(1):55-61.
Reinsborough C, Chess A. An epigenetic trap involved in olfactory receptor gene choice. Dev Cell 2013 Jul 29;26(2):120-1.
Chess A. Mechanisms and consequences of widespread random monoallelic expression. Nat Rev Genet 2012 Jun;13(6):421-8.
Zwemer LM, Zak A, Thompson BR, Kirby A, Daly MJ, Chess A, Gimelbrant AA. Autosomal monoallelic expression in the mouse. Genome Biol 2012;13(2):R10.
Fang G, Munera D, Friedman DI, Mandlik A, Chao MC, Banerjee O, Feng Z, Losic B, Mahajan MC, Jabado OJ, Deikus G, Clark TA, Luong K, Murray IA, Davis BM, Keren-Paz A, Chess A, Roberts RJ, Korlach J, Turner SW, Kumar V, Waldor MK, Schadt EE. Genome-wide mapping of methylated adenine residues in pathogenic Escherichia coli using single-molecule real-time sequencing. Nat Biotechnol 2012 Dec;30(12):1232-9.
Shen WL, Kwon Y, Adegbola AA, Luo J, Chess A, Montell C. Function of rhodopsin in temperature discrimination in Drosophila. Science 2011 Mar 11;331(6022):1333-6.