Nashville, TN 37232-0146
DNA methylation and Chromatin Dynamics
In recent work, we showed that DNA methylation dynamics are temporally distinct from chromatin and transcriptional changes that drive cell differentiation. Instead, we showed that long-lasting de-methylation of distinct gene enhancer combinations at specific developmental time points reinforces cell fate choices to create historical records of a cell’s journey through development (Scott et al., 2023, Guerin et al., 2025). We can now use this knowledge to build models that predict cell origins and fates from DNA methylation patterns, as well as to understand why perturbations to DNA methylation lead to failures in normal cell differentiation.
Epigenetics and EHRs
We use human population genetics and Electronic Health Records (EHRs) to understand the clinical significance of DNA methylation patterns and their underlying DNA sequences (Scott et al., 2023). EHRs provide an extensive repository of phenotypic conditions which we leveraged to discover previously unknown mechanistic links between the non-coding genome and clinical outcomes. Using our approach, we identified a novel B cell enhancer cluster that regulates lymphocyte production and harbors genetic variants linked to lymphocytic leukemia risk (Day et al. 2025, in prep). In pancreatic islets, we discovered a previously unidentified regulator of PAM, a gene involved in insulin secretion of pancreatic beta cells with strong links to Type 2 diabetes (Agan et al., 2025, in prep). These are just two of thousands of non-coding loci identified by our approach, which can be broadly applied across organ systems and disease contexts.
Understanding gene regulatory divergence between species
DNA sequence and cell environment changes contribute to differences between individuals and species. We developed a genome-scale reporter technology (Hansen and Hodges, 2022) to directly disentangle the effects of these two mechanisms (sequence vs. environment) on gene regulatory activity between human and rhesus macaque lymphocytes - all from a single assay. Differences between species are often attributed to sequence variation, but we uncovered a substantial role for cell environment differences in driving gene regulatory divergence (Hansen, Fong et al., 2024). Current and future work will extend our findings beyond that of human evolution to understand how these individual mechanisms contribute to differences in human disease risk. These questions are pertinent to diseases like cancer, where the interplay between sequence changes, epigenetics and cellular environment strongly impacts disease outcomes.
Liu J, Banerjee A, Herring CA, Attalla J, Hu R, Xu Y, Shao Q, Simmons AJ, Dadi PK, Wang S, Jacobson DA, Liu B, Hodges E, Lau KS, Gu G. Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity. Dev. Cell. 2019 Jan 1/7/2019; 48(1): 49-63.e7. PMID: 30620902, PMCID: PMC6327977, PII: S1534-5807(18)31032-3, DOI: 10.1016/j.devcel.2018.11.048, ISSN: 1878-1551.
Boothby MR, Hodges E, Thomas JW. Molecular regulation of peripheral B cells and their progeny in immunity. Genes Dev. 2019 Jan 1/1/2019; 33(1-2): 26-48. PMID: 30602439, PMCID: PMC6317321, PII: 33/1-2/26, DOI: 10.1101/gad.320192.118, ISSN: 1549-5477.
Qu J, Hodges E, Molaro A, Gagneux P, Dean MD, Hannon GJ, Smith AD. Evolutionary expansion of DNA hypomethylation in the mammalian germline genome. Genome Res [print-electronic]. 2018 Feb; 28(2): 145-58. PMID: 29259021, PMCID: PMC5793779, PII: gr.225896.117, DOI: 10.1101/gr.225896.117, ISSN: 1549-5469.
Stengel KR, Barnett KR, Wang J, Liu Q, Hodges E, Hiebert SW, Bhaskara S. Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2017 Aug 8/8/2017; 114(32): 8608-13. PMID: 28739911, PMCID: PMC5559004, PII: 1701610114, DOI: 10.1073/pnas.1701610114, ISSN: 1091-6490.
Chang D, Knapp M, Enk J, Lippold S, Kircher M, Lister A, MacPhee RD, Widga C, Czechowski P, Sommer R, Hodges E, Stümpel N, Barnes I, Dalén L, Derevianko A, Germonpré M, Hillebrand-Voiculescu A, Constantin S, Kuznetsova T, Mol D, Rathgeber T, Rosendahl W, Tikhonov AN, Willerslev E, Hannon G, Lalueza-Fox C, Joger U, Poinar H, Hofreiter M, Shapiro B. The evolutionary and phylogeographic history of woolly mammoths: a comprehensive mitogenomic analysis. Sci Rep. 2017 Mar 3/22/2017; 7: 44585. PMID: 28327635, PII: srep44585, DOI: 10.1038/srep44585, ISSN: 2045-2322.
McFadden DG, Politi K, Bhutkar A, Chen FK, Song X, Pirun M, Santiago PM, Kim-Kiselak C, Platt JT, Lee E, Hodges E, Rosebrock AP, Bronson RT, Socci ND, Hannon GJ, Jacks T, Varmus H. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2016 Oct 10/18/2016; 113(42): E6409-E6417. PMID: 27702896, PMCID: PMC5081629, PII: 1613601113, DOI: 10.1073/pnas.1613601113, ISSN: 1091-6490.
Dos Santos CO, Dolzhenko E, Hodges E, Smith AD, Hannon GJ. An epigenetic memory of pregnancy in the mouse mammary gland. Cell Rep [print-electronic]. 2015 May 5/19/2015; 11(7): 1102-9. PMID: 25959817, PMCID: PMC4439279, PII: S2211-1247(15)00390-3, DOI: 10.1016/j.celrep.2015.04.015, ISSN: 2211-1247.
Malaspinas AS, Lao O, Schroeder H, Rasmussen M, Raghavan M, Moltke I, Campos PF, Sagredo FS, Rasmussen S, Gonçalves VF, Albrechtsen A, Allentoft ME, Johnson PL, Li M, Reis S, Bernardo DV, DeGiorgio M, Duggan AT, Bastos M, Wang Y, Stenderup J, Moreno-Mayar JV, Brunak S, Sicheritz-Ponten T, Hodges E, Hannon GJ, Orlando L, Price TD, Jensen JD, Nielsen R, Heinemeier J, Olsen J, Rodrigues-Carvalho C, Lahr MM, Neves WA, Kayser M, Higham T, Stoneking M, Pena SD, Willerslev E. Two ancient human genomes reveal Polynesian ancestry among the indigenous Botocudos of Brazil [letter]. Curr. Biol [print-electronic]. 2014 Nov 11/3/2014; 24(21): R1035-7. PMID: 25455029, PMCID: PMC4370112, PII: S0960-9822(14)01274-3, DOI: 10.1016/j.cub.2014.09.078, ISSN: 1879-0445.
Molaro A, Falciatori I, Hodges E, Aravin AA, Marran K, Rafii S, McCombie WR, Smith AD, Hannon GJ. Two waves of de novo methylation during mouse germ cell development. Genes Dev. 2014 Jul 7/15/2014; 28(14): 1544-9. PMID: 25030694, PMCID: PMC4102761, PII: 28/14/1544, DOI: 10.1101/gad.244350.114, ISSN: 1549-5477.
Schlesinger F, Smith AD, Gingeras TR, Hannon GJ, Hodges E. De novo DNA demethylation and noncoding transcription define active intergenic regulatory elements. Genome Res [print-electronic]. 2013 Oct; 23(10): 1601-14. PMID: 23811145, PMCID: PMC3787258, PII: gr.157271.113, DOI: 10.1101/gr.157271.113, ISSN: 1549-5469.
Wiggs JL, Howell GR, Linkroum K, Abdrabou W, Hodges E, Braine CE, Pasquale LR, Hannon GJ, Haines JL, John SW. Variations in COL15A1 and COL18A1 influence age of onset of primary open angle glaucoma. Clin. Genet [print-electronic]. 2013 Aug; 84(2): 167-74. PMID: 23621901, PMCID: PMC3771394, DOI: 10.1111/cge.12176, ISSN: 1399-0004.
Uren PJ, Bahrami-Samani E, Burns SC, Qiao M, Karginov FV, Hodges E, Hannon GJ, Sanford JR, Penalva LO, Smith AD. Site identification in high-throughput RNA-protein interaction data. Bioinformatics [print-electronic]. 2012 Dec 12/1/2012; 28(23): 3013-20. PMID: 23024010, PMCID: PMC3509493, PII: bts569, DOI: 10.1093/bioinformatics/bts569, ISSN: 1367-4811.
Fang F, Hodges E, Molaro A, Dean M, Hannon GJ, Smith AD. Genomic landscape of human allele-specific DNA methylation. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2012 May 5/8/2012; 109(19): 7332-7. PMID: 22523239, PMCID: PMC3358917, PII: 1201310109, DOI: 10.1073/pnas.1201310109, ISSN: 1091-6490.
Hodges E, Molaro A, Dos Santos CO, Thekkat P, Song Q, Uren PJ, Park J, Butler J, Rafii S, McCombie WR, Smith AD, Hannon GJ. Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment. Mol. Cell [print-electronic]. 2011 Oct 10/7/2011; 44(1): 17-28. PMID: 21924933, PMCID: PMC3412369, PII: S1097-2765(11)00676-9, DOI: 10.1016/j.molcel.2011.08.026, ISSN: 1097-4164.
Molaro A, Hodges E, Fang F, Song Q, McCombie WR, Hannon GJ, Smith AD. Sperm methylation profiles reveal features of epigenetic inheritance and evolution in primates. Cell. 2011 Sep 9/16/2011; 146(6): 1029-41. PMID: 21925323, PMCID: PMC3205962, PII: S0092-8674(11)00942-1, DOI: 10.1016/j.cell.2011.08.016, ISSN: 1097-4172.
Albert FW, Hodges E, Jensen JD, Besnier F, Xuan Z, Rooks M, Bhattacharjee A, Brizuela L, Good JM, Green RE, Burbano HA, Plyusnina IZ, Trut L, Andersson L, Schöneberg T, Carlborg O, Hannon GJ, Pääbo S. Targeted resequencing of a genomic region influencing tameness and aggression reveals multiple signals of positive selection. Heredity (Edinb) [print-electronic]. 2011 Sep; 107(3): 205-14. PMID: 21304545, PMCID: PMC3183948, PII: hdy20114, DOI: 10.1038/hdy.2011.4, ISSN: 1365-2540.
Erlich Y, Edvardson S, Hodges E, Zenvirt S, Thekkat P, Shaag A, Dor T, Hannon GJ, Elpeleg O. Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis. Genome Res [print-electronic]. 2011 May; 21(5): 658-64. PMID: 21487076, PMCID: PMC3083082, PII: gr.117143.110, DOI: 10.1101/gr.117143.110, ISSN: 1549-5469.
Lachke SA, Alkuraya FS, Kneeland SC, Ohn T, Aboukhalil A, Howell GR, Saadi I, Cavallesco R, Yue Y, Tsai AC, Nair KS, Cosma MI, Smith RS, Hodges E, Alfadhli SM, Al-Hajeri A, Shamseldin HE, Behbehani A, Hannon GJ, Bulyk ML, Drack AV, Anderson PJ, John SW, Maas RL. Mutations in the RNA granule component TDRD7 cause cataract and glaucoma. Science. 2011 Mar 3/25/2011; 331(6024): 1571-6. PMID: 21436445, PMCID: PMC3279122, PII: 331/6024/1571, DOI: 10.1126/science.1195970, ISSN: 1095-9203.
Igartua C, Turner EH, Ng SB, Hodges E, Hannon GJ, Bhattacharjee A, Rieder MJ, Nickerson DA, Shendure J. Targeted enrichment of specific regions in the human genome by array hybridization. Curr Protoc Hum Genet. 2010 Jul; Chapter 18: Unit 18.3. PMID: 20582915, PMCID: PMC2910258, DOI: 10.1002/0471142905.hg1803s66, ISSN: 1934-8258.
Burbano HA, Hodges E, Green RE, Briggs AW, Krause J, Meyer M, Good JM, Maricic T, Johnson PL, Xuan Z, Rooks M, Bhattacharjee A, Brizuela L, Albert FW, de la Rasilla M, Fortea J, Rosas A, Lachmann M, Hannon GJ, Pääbo S. Targeted investigation of the Neandertal genome by array-based sequence capture. Science. 2010 May 5/7/2010; 328(5979): 723-5. PMID: 20448179, PMCID: PMC3140021, PII: 328/5979/723, DOI: 10.1126/science.1188046, ISSN: 1095-9203.
Rosa-Rosa JM, Gracia-Aznárez FJ, Hodges E, Pita G, Rooks M, Xuan Z, Bhattacharjee A, Brizuela L, Silva JM, Hannon GJ, Benitez J. Deep sequencing of target linkage assay-identified regions in familial breast cancer: methods, analysis pipeline and troubleshooting. PLoS ONE. 2010; 5(4): e9976. PMID: 20368986, PMCID: PMC2848842, DOI: 10.1371/journal.pone.0009976, ISSN: 1932-6203.
Berezikov E, Liu N, Flynt AS, Hodges E, Rooks M, Hannon GJ, Lai EC. Evolutionary flux of canonical microRNAs and mirtrons in Drosophila [letter]. Nat. Genet. 2010 Jan; 42(1): 6-9; author reply 9. PMID: 20037610, PMCID: PMC4136759, PII: ng0110-6, DOI: 10.1038/ng0110-6, ISSN: 1546-1718.
Smith AD, Chung WY, Hodges E, Kendall J, Hannon G, Hicks J, Xuan Z, Zhang MQ. Updates to the RMAP short-read mapping software. Bioinformatics [print-electronic]. 2009 Nov 11/1/2009; 25(21): 2841-2. PMID: 19736251, PMCID: PMC2895571, PII: btp533, DOI: 10.1093/bioinformatics/btp533, ISSN: 1367-4811.
Hodges E, Smith AD, Kendall J, Xuan Z, Ravi K, Rooks M, Zhang MQ, Ye K, Bhattacharjee A, Brizuela L, McCombie WR, Wigler M, Hannon GJ, Hicks JB. High definition profiling of mammalian DNA methylation by array capture and single molecule bisulfite sequencing. Genome Res [print-electronic]. 2009 Sep; 19(9): 1593-605. PMID: 19581485, PMCID: PMC2752124, PII: gr.095190.109, DOI: 10.1101/gr.095190.109, ISSN: 1549-5469.
Hodges E, Rooks M, Xuan Z, Bhattacharjee A, Benjamin Gordon D, Brizuela L, Richard McCombie W, Hannon GJ. Hybrid selection of discrete genomic intervals on custom-designed microarrays for massively parallel sequencing. Nat Protoc [print-electronic]. 2009; 4(6): 960-74. PMID: 19478811, PMCID: PMC2990409, PII: nprot.2009.68, DOI: 10.1038/nprot.2009.68, ISSN: 1750-2799.
Murchison EP, Kheradpour P, Sachidanandam R, Smith C, Hodges E, Xuan Z, Kellis M, Grützner F, Stark A, Hannon GJ. Conservation of small RNA pathways in platypus. Genome Res [print-electronic]. 2008 Jun; 18(6): 995-1004. PMID: 18463306, PMCID: PMC2413167, PII: gr.073056.107, DOI: 10.1101/gr.073056.107, ISSN: 1088-9051.
Tam OH, Aravin AA, Stein P, Girard A, Murchison EP, Cheloufi S, Hodges E, Anger M, Sachidanandam R, Schultz RM, Hannon GJ. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature [print-electronic]. 2008 May 5/22/2008; 453(7194): 534-8. PMID: 18404147, PMCID: PMC2981145, PII: nature06904, DOI: 10.1038/nature06904, ISSN: 1476-4687.
Mi S, Cai T, Hu Y, Chen Y, Hodges E, Ni F, Wu L, Li S, Zhou H, Long C, Chen S, Hannon GJ, Qi Y. Sorting of small RNAs into Arabidopsis argonaute complexes is directed by the 5' terminal nucleotide. Cell [print-electronic]. 2008 Apr 4/4/2008; 133(1): 116-27. PMID: 18342361, PMCID: PMC2981139, PII: S0092-8674(08)00285-7, DOI: 10.1016/j.cell.2008.02.034, ISSN: 1097-4172.
Hodges E, Xuan Z, Balija V, Kramer M, Molla MN, Smith SW, Middle CM, Rodesch MJ, Albert TJ, Hannon GJ, McCombie WR. Genome-wide in situ exon capture for selective resequencing. Nat. Genet [print-electronic]. 2007 Dec; 39(12): 1522-7. PMID: 17982454, PII: ng.2007.42, DOI: 10.1038/ng.2007.42, ISSN: 1546-1718.
Stark A, Kheradpour P, Parts L, Brennecke J, Hodges E, Hannon GJ, Kellis M. Systematic discovery and characterization of fly microRNAs using 12 Drosophila genomes. Genome Res [print-electronic]. 2007 Dec; 17(12): 1865-79. PMID: 17989255, PMCID: PMC2099594, PII: gr.6593807, DOI: 10.1101/gr.6593807, ISSN: 1088-9051.
Stark A, Lin MF, Kheradpour P, Pedersen JS, Parts L, Carlson JW, Crosby MA, Rasmussen MD, Roy S, Deoras AN, Ruby JG, Brennecke J, , , Hodges E, Hinrichs AS, Caspi A, Paten B, Park SW, Han MV, Maeder ML, Polansky BJ, Robson BE, Aerts S, van Helden J, Hassan B, Gilbert DG, Eastman DA, Rice M, Weir M, Hahn MW, Park Y, Dewey CN, Pachter L, Kent WJ, Haussler D, Lai EC, Bartel DP, Hannon GJ, Kaufman TC, Eisen MB, Clark AG, Smith D, Celniker SE, Gelbart WM, Kellis M. Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures. Nature. 2007 Nov 11/8/2007; 450(7167): 219-32. PMID: 17994088, PMCID: PMC2474711, PII: nature06340, DOI: 10.1038/nature06340, ISSN: 1476-4687.
Postdoctoral Position - Epigenomics and Gene Regulation
A postdoctoral position is immediately available at the Vanderbilt University Genetics Institute and Department of Biochemistry. Our group is interested in the role of non-coding sequence variation in complex disease. Research in the Hodges Lab strives to understand how epigenetic features shape human genomes. Our work aims to dissect the relationship between DNA methylation and gene regulation, particularly with respect to the gene regulatory activity of non-coding functional elements. We study this relationship on two levels; first, we are interested in how DNA methylation states are established in differentiating cells. Second, we are interested in the relationship between genotype and DNA methylation state (epitype). Projects in our lab address these questions utilizing innovative biochemical, functional genomic and bioinformatic approaches. The successful candidate will have a strong molecular biology background. Experience with next-generation sequencing, statistical genetics, and bioinformatics is a priority. Please send CVs along with contact info for three references to emily.hodges"at"vanderbilt.edu
