Mahesh B. Chandrasekharan

Mahesh B. Chandrasekharan, PhD, MS

Languages spoken: Hindi, Kannada, Malayalam, Tamil, Telugu, Tulu, English

Academic Information

Departments Primary - Radiation Oncology

Divisions: Hematology & Hematologic Malignancies

Lab

Research Interests

  • Cancer Biology
  • Cancer Therapeutics
  • Histone Modifications
  • Transcription
  • Genome Stability

Dr. Chandrasekharan received his PhD in Biology in 2001 from Texas A&M University, College Station, TX. He then completed a postdoctoral fellowship at Vanderbilt University Medical Center in Nashville, TN. Currently, Dr. Chandrasekharan is an Assistant Professor in the Department of Radiation Oncology and an Adjunct Assistant Professor in the Division of Hematology & Hematological Malignancies within the Department of Internal Medicine. He is also an Investigator at the Huntsman Cancer Institute and a member of the Nuclear Control of Cell Growth and Differentiation program.

Dr. Chandrasekharan’s research focuses on the regulation and functions of epigenetic mechanisms and protein homeostasis, which together control nearly all aspects of organismal and cellular development, often going awry in cancers. He employs yeast, cultured mammalian cells, and mice as model systems for both fundamental and cancer-focused studies. His research utilizes a range of methodologies, including structural, biochemical, genetic, and genomic/proteomic approaches.

As a graduate student, Dr. Chandrasekharan investigated the role of chromatin in the spatio-temporal regulation of gene expression during development. His postdoctoral research focused on the evolutionarily conserved crosstalk between histone H2B monoubiquitination and the methylation of histone H3 at lysines 4 and 79 (H3K4 and H3K79). A significant discovery during his postdoctoral studies was that histone H2B ubiquitination stabilizes the nucleosome. He also identified that the H2B C-terminal helix modulates H3K4 methylation independently of H2B ubiquitination by serving as a ‘docking site’ for Set1-COMPASS, a methyltransferase-containing complex. As an independent investigator, Dr. Chandrasekharan aims to build upon these works to further elucidate the complexities of trans-histone crosstalk between H2B ubiquitination and H3 methylation. His research also delves into the intricacies of protein turnover or homeostasis (proteostasis) through ubiquitin conjugation.

Histone-modifying enzymes, particularly those involved in the aforementioned trans-histone crosstalk, have garnered significant interest due to their implications in various human diseases, including cancers. The link between dysregulated protein homeostasis mechanisms and cancer is also well established, as exemplified by oncogenic mutations in the BRCA1 E3 ubiquitin ligase. Dr. Chandrasekharan’s current research goals are two-fold: First, he seeks to understand the fundamental mechanisms regulating the functions of histone- and protein-modifying enzymes. Second, he aims to leverage insights gained from these studies to better understand disease formation and progression, ultimately contributing to the development of effective cancer therapeutics.

Education History

Postdoctoral Fellowship Vanderbilt University School of Medicine
 Postdoctoral Fellow
Fellowship Institute of Developmental and Molecular Biology, Texas A&M University
 Postdoctoral Research Associate
Doctoral Training Texas A&M University
 PhD
Graduate Training Madurai Kamaraj University
 MS
Undergraduate St. Aloysius College, University of Mangalore
 BS

Selected Publications

Journal Article

  1. Wu Y, Manna AK, Li L, Handa H, Chandrasekharan MB, Tantin D (2024). Jade1 and the HBO1 complex are spatial-selective cofactors of Oct4. bioRxiv. (Read full article)
  2. Shen Z, Wu Y, Manna A, Yi C, Cairns BR, Evason KJ, Chandrasekharan MB, Tantin D (2024). Oct4 redox sensitivity potentiates reprogramming and differentiation. Genes Dev, 38(7-8), 308-321. (Read full article)
  3. Radmall KS, Shukla PK, Leng AM, Chandrasekharan MB (2023). Structure-function analysis of histone H2B and PCNA ubiquitination dynamics using deubiquitinase-deficient strains. Sci Rep, 13(1), 16731. (Read full article)
  4. Shukla PK, Radmall KS, Chandrasekharan MB (2023). Rapid purification of rabbit immunoglobulins using a single-step, negative-selection chromatography. Protein Expr Purif, 207, 106270. (Read full article)
  5. Perovanovic J, Wu Y, Abewe H, Shen Z, Hughes EP, Gertz J, Chandrasekharan MB, Tantin D (2023). Oct1 cooperates with the Smad family of transcription factors to promote mesodermal lineage specification. Sci Signal, 16(781), eadd5750. (Read full article)
  6. Shukla PK, Bissell JE, Kumar S, Pokhrel S, Palani S, Radmall KS, Obidi O, Parnell TJ, Brasch J, Shrieve DC, Chandrasekharan MB (2023). Structure and functional determinants of Rad6-Bre1 subunits in the histone H2B ubiquitin-conjugating complex. Nucleic Acids Res, 51(5), 2117-2136. (Read full article)
  7. Shukla PK, Sinha D, Leng AM, Bissell JE, Thatipamula S, Ganguly R, Radmall KS, Skalicky JJ, Shrieve DC, Chandrasekharan MB (2022). Mutations of Rad6 E2 ubiquitin-conjugating enzymes at alanine-126 in helix-3 affect ubiquitination activity and decrease enzyme stability. J Biol Chem, 298(11), 102524. (Read full article)
  8. Leng AM, Radmall KS, Shukla PK, Chandrasekharan MB (2022). Quantitative Assessment of Histone H2B Monoubiquitination in Yeast Using Immunoblotting. Methods Protoc, 5(5). (Read full article)
  9. Hess L, Moos V, Lauber AA, Reiter W, Schuster M, Hartl N, Lackner D, Boenke T, Koren A, Guzzardo PM, Gundacker B, Riegler A, Vician P, Miccolo C, Leiter S, Chandrasekharan MB, Vcelkova T, Tanzer A, Jun JQ, Bradner J, Brosch G, Hartl M, Bock C, Brckstmmer T, Kubicek S, Chiocca S, Bhaskara S, Seiser C (2022). A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation. PLoS Genet, 18(8), e1010376. (Read full article)
  10. Tan Y, Schneider T, Shukla PK, Chandrasekharan MB, Aravind L, Zhang D (2021). Unification and extensive diversification of M/Orf3-related ion channel proteins in coronaviruses and other nidoviruses. Virus Evol, 7(1), veab014. (Read full article)
  11. Johnson DP, Chandrasekharan MB, Dutreix M, Bhaskara S (2021). Targeting DNA Repair and Chromatin Crosstalk in Cancer Therapy. Cancers (Basel), 13(3). (Read full article)
  12. Tiburcio PDB, Locke MC, Bhaskara S, Chandrasekharan MB, Huang LE (2020). The neural stem-cell marker CD24 is specifically upregulated in IDH-mutant glioma. Transl Oncol, 13(10), 100819. (Read full article)
  13. Meriesh HA, Lerner AM, Chandrasekharan MB, Strahl BD (2020). The histone H4 basic patch regulates SAGA-mediated H2B deubiquitination and histone acetylation. J Biol Chem, 295(19), 6561-6569. (Read full article)
  14. McCullough LL, Pham TH, Parnell TJ, Connell Z, Chandrasekharan MB, Stillman DJ, Formosa T (2019). Establishment and Maintenance of Chromatin Architecture Are Promoted Independently of Transcription by the Histone Chaperone FACT and H3-K56 Acetylation in Saccharomyces cerevisiae. Genetics, 211(3), 877-892. (Read full article)
  15. Tharkar-Promod S, Johnson DP, Bennett SE, Dennis EM, Banowsky BG, Jones SS, Shearstone JR, Quayle SN, Min C, Jarpe M, Mosbruger T, Pomicter AD, Miles RR, Chen WY, Bhalla KN, Zweidler-McKay PA, Shrieve DC, Deininger MW, Chandrasekharan MB, Bhaskara S (2017). HDAC1,2 inhibition and doxorubicin impair Mre11-dependent DNA repair and DISC to override BCR-ABL1-driven DSB repair in Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia. Leukemia, 32(1), 49-60. (Read full article)
  16. Sdano MA, Fulcher JM, Palani S, Chandrasekharan MB, Parnell TJ, Whitby FG, Formosa T, Hill CP (2017). A novel SH2 recognition mechanism recruits Spt6 to the doubly phosphorylated RNA polymerase II linker at sites of transcription. Elife, 6. (Read full article)
  17. Ramakrishnan S, Pokhrel S, Palani S, Pflueger C, Parnell TJ, Cairns BR, Bhaskara S, Chandrasekharan MB (2016). Counteracting H3K4 methylation modulators Set1 and Jhd2 co-regulate chromatin dynamics and gene transcription. Nat Commun, 7, 11949. (Read full article)
  18. Andrade D, Velinder M, Singer J, Maese L, Bareyan D, Nguyen H, Chandrasekharan MB, Lucente H, McClellan D, Jones D, Sharma S, Liu F, Engel ME (2016). SUMOylation Regulates Growth Factor Independence 1 in Transcriptional Control and Hematopoiesis. Mol Cell Biol, 36(10), 1438-50. (Read full article)
  19. Huang F, Ramakrishnan S, Pokhrel S, Pflueger C, Parnell TJ, Kasten MM, Currie SL, Bhachech N, Horikoshi M, Graves BJ, Cairns BR, Bhaskara S, Chandrasekharan MB (2015). Interaction of the Jhd2 Histone H3 Lys-4 Demethylase with Chromatin Is Controlled by Histone H2A Surfaces and Restricted by H2B Ubiquitination. J Biol Chem, 290(48), 28760-77. (Read full article)
  20. Johnson DP, Spitz GS, Tharkar S, Quayle SN, Shearstone JR, Jones S, McDowell ME, Wellman H, Tyler JK, Cairns BR, Chandrasekharan MB, Bhaskara S (2015). HDAC1,2 inhibition impairs EZH2- and BBAP-mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma. Oncotarget, 6(7), 4863-87. (Read full article)
  21. Bhaskara S, Jacques V, Rusche JR, Olson EN, Cairns BR, Chandrasekharan MB (2013). Histone deacetylases 1 and 2 maintain S-phase chromatin and DNA replication fork progression. Epigenetics Chromatin, 6(1), 27. (Read full article)
  22. Chandrasekharan MB, Huang F, Sun ZW (2011). Decoding the trans-histone crosstalk: methods to analyze H2B ubiquitination, H3 methylation and their regulatory factors. Methods, 54(3), 304-14. (Read full article)
  23. Joo HY, Jones A, Yang C, Zhai L, Smith AD 4th, Zhang Z, Chandrasekharan MB, Sun ZW, Renfrow MB, Wang Y, Chang C, Wang H (2011). Regulation of histone H2A and H2B deubiquitination and Xenopus development by USP12 and USP46. J Biol Chem, 286(9), 7190-201. (Read full article)
  24. Bhaskara S, Knutson SK, Jiang G, Chandrasekharan MB, Wilson AJ, Zheng S, Yenamandra A, Locke K, Yuan JL, Bonine-Summers AR, Wells CE, Kaiser JF, Washington MK, Zhao Z, Wagner FF, Sun ZW, Xia F, Holson EB, Khabele D, Hiebert SW (2010). Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell, 18(5), 436-47. (Read full article)
  25. Huang F, Chandrasekharan MB, Chen YC, Bhaskara S, Hiebert SW, Sun ZW (2010). The JmjN domain of Jhd2 is important for its protein stability, and the plant homeodomain (PHD) finger mediates its chromatin association independent of H3K4 methylation. J Biol Chem, 285(32), 24548-61. (Read full article)
  26. Chandrasekharan MB, Huang F, Chen YC, Sun ZW (2010). Histone H2B C-terminal helix mediates trans-histone H3K4 methylation independent of H2B ubiquitination. Mol Cell Biol, 30(13), 3216-32. (Read full article)
  27. Chandrasekharan MB, Huang F, Sun ZW (2009). Ubiquitination of histone H2B regulates chromatin dynamics by enhancing nucleosome stability. Proc Natl Acad Sci U S A, 106(39), 16686-91. (Read full article)
  28. Nakanishi S, Lee JS, Gardner KE, Gardner JM, Takahashi YH, Chandrasekharan MB, Sun ZW, Osley MA, Strahl BD, Jaspersen SL, Shilatifard A (2009). Histone H2BK123 monoubiquitination is the critical determinant for H3K4 and H3K79 trimethylation by COMPASS and Dot1. J Cell Biol, 186(3), 371-7. (Read full article)
  29. Bhaskara S, Chandrasekharan MB, Ganguly R (2008). Caffeine induction of Cyp6a2 and Cyp6a8 genes of Drosophila melanogaster is modulated by cAMP and D-JUN protein levels. Gene, 415(1-2), 49-59. (Read full article)
  30. Bradley C, van der Meer R, Roodi N, Yan H, Chandrasekharan MB, Sun ZW, Mernaugh RL, Parl FF (2007). Carcinogen-induced histone alteration in normal human mammary epithelial cells. Carcinogenesis, 28(10), 2184-92. (Read full article)
  31. Ng DW, Chandrasekharan MB, Hall TC (2006). Ordered histone modifications are associated with transcriptional poising and activation of the phaseolin promoter. Plant Cell, 18(1), 119-32. (Read full article)
  32. Zhou X, Chandrasekharan MB, Hall TC (2021). High rooting frequency and functional analysis of GUS and GFP expression in transgenic Medicago truncatula A17. New Phytol, 162(3), 813-822. (Read full article)
  33. Carranco R, Chandrasekharan MB, Townsend JC, Hall TC (2004). Interaction of PvALF and VP1 B3 domains with the beta -phaseolin promoter. Plant Mol Biol, 55(2), 221-37. (Read full article)
  34. Grace ML, Chandrasekharan MB, Hall TC, Crowe AJ (2004). Sequence and spacing of TATA box elements are critical for accurate initiation from the beta-phaseolin promoter. J Biol Chem, 279(9), 8102-10. (Read full article)
  35. Ng DW, Chandrasekharan MB, Hall TC (2004). The 5' UTR negatively regulates quantitative and spatial expression from the ABI3 promoter. Plant Mol Biol, 54(1), 25-38. (Read full article)
  36. Teerawanichpan P, Chandrasekharan MB, Jiang Y, Narangajavana J, Hall TC (2004). Characterization of two rice DNA methyltransferase genes and RNAi-mediated reactivation of a silenced transgene in rice callus. Planta, 218(3), 337-49. (Read full article)
  37. Chandrasekharan MB, Li G, Bishop KJ, Hall TC (2003). S phase progression is required for transcriptional activation of the beta-phaseolin promoter. J Biol Chem, 278(46), 45397-405. (Read full article)
  38. Chandrasekharan MB, Bishop KJ, Hall TC (2003). Module-specific regulation of the beta-phaseolin promoter during embryogenesis. Plant J, 33(5), 853-66. (Read full article)
  39. Yang G, Dong J, Chandrasekharan MB, Hall TC (2001). Kiddo, a new transposable element family closely associated with rice genes. Mol Genet Genomics, 266(3), 417-24. (Read full article)
  40. Li G, Bishop KJ, Chandrasekharan MB, Hall TC (1999). beta-Phaseolin gene activation is a two-step process: PvALF- facilitated chromatin modification followed by abscisic acid-mediated gene activation. Proc Natl Acad Sci U S A, 96(12), 7104-9. (Read full article)
  41. Hall TC, Li G, Chandrasekharan MB (1998). Participation of chromatin in the regulation of phaseolin gene expression. J Plant Physiol, 152, 614-620.

Review

  1. Chandrasekharan MB, Huang F, Sun ZW (2010). Histone H2B ubiquitination and beyond: Regulation of nucleosome stability, chromatin dynamics and the trans-histone H3 methylation. [Review]. Epigenetics, 5(6), 460-8. (Read full article)
  2. Ng DW, Wang T, Chandrasekharan MB, Aramayo R, Kertbundit S, Hall TC (2007). Plant SET domain-containing proteins: structure, function and regulation. [Review]. Biochim Biophys Acta, 1769(5-6), 316-29. (Read full article)
  3. Li G, Chandrasekharan MB, Wolffe AP, Hall TC (2001). Chromatin structure and phaseolin gene regulation. [Review]. Plant Mol Biol, 46(2), 121-9. (Read full article)
  4. Iyer LM, Kumpatla SP, Chandrasekharan MB, Hall TC (2000). Transgene silencing in monocots. [Review]. Plant Mol Biol, 43(2-3), 323-46. (Read full article)
  5. Kumpatla SP, Chandrasekharan MB, Iyer LM, Li G, Hall TC (1998). Genome intruder scanning and modulation systems and transgene silencing. [Review]. Trends Plant Sci, 3, 97-104.

Book Chapter

  1. Hall TC, Chandrasekharan MB, Li G (1999). Phaseolin: its past, properties, regulation and future. In Casey R, Shewry PR (Eds.), Seed Proteins (pp. 209-240). The Netherlands: Kluwer, Dorderecht.