Mahesh B. Chandrasekharan

Mahesh B. Chandrasekharan, PhD

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

Academic Information

Departments Primary - Radiation Oncology

Academic Office Information

Mahesh.Chandrasekharan@hci.utah.edu

Lab

Research Interests

  • Histone Modifications
  • Transcription
  • Genome Stability

Dr. Chandrasekharan received his PhD in Biology in 2001 from Texas A&M University, College Station, TX. He was a post-doctoral fellow at Vanderbilt University Medical Center in Nashville, TN in Dr. Zu-Wen Sun's lab until 2011. He is currently an Assistant Professor in the Department of Radiation Oncology, and Investigator at Huntsman Cancer Institute, and a member of the Nuclear Control of Cell Growth and Differentiation program.


Dr. Chandrasekharan was awarded MS (Biotechnology) Merit Scholarship by the Department of Biotechnology, Government of India, in 1991 and Biology Doctoral Merit Award by the Department of Biology, Texas A&M University, College Station, TX.


Dr. Chandrasekharan’s research focus is to understand the regulation and functions of histone modifications that act as epigenetic mechanism and protein homeostasis mechanism, which together control nearly all aspects of organismal and cellular development, and frequently go awry in cancers. He uses budding yeast and mammalian cell culture as model systems of choice for his fundamental as well as cancer-focused studies.


As a graduate student, he investigated how chromatin plays an important role in the spatio-temporal regulation of gene expression during development. His post-doctoral research was to understand the regulation and functions of the evolutionarily conserved crosstalk between histone H2B monoubiquitination and histone H3 lysine-4 and lysine-79 (K4 and K79) methylation. During the course of his post-doctoral studies, he made a novel and rather unexpected discovery that histone H2B ubiquitination stabilizes the nucleosome. He also found that the H2B C-terminal helix modulates H3K4 methylation independent of H2B ubiquitination, by providing a ‘docking site’ for Set1-COMPASS (the methyltransferase-containing complex). As an independent investigator, the primary research objective of his laboratory is to continue his post-doctoral work and further understand the intricacies of the trans-histone crosstalk between H2B ubiquitination and H3 methylation using a structural, biochemical, genetics and genomics based combinatorial approach. His independent research also investigates the intricacies of protein turnover or homeostasis (proteostasis) via ubiquitin conjugation.


Histone-modifying enzymes including those involved in the aforementioned trans-histone crosstalk have garnered much interest in recent times, as they have been implicated in many human diseases including cancers. Also, the connection between deregulated protein homeostasis mechanisms and cancers is well established -- as exemplified by the oncogenic mutations in BRCA1 E3 ubiquitin ligase. Dr. Chandrasekharan’s current research goal is two-fold: first, he intends to understand the fundamental mechanisms of regulation and functions of histone- or protein-modifying enzymes. Second, he intends to utilize the knowledge gained from his studies of fundamental mechanisms to obtain insight into disease formation and progression, and develop effective therapeutics for cancer treatment.

Education History

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

Selected Publications

Journal Article

  1. 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.
  2. Shukla PK, Radmall KS, Chandrasekharan MB (2023). Rapid purification of rabbit immunoglobulins using a single-step, negative-selection chromatography. Protein Expr Purif, 207, 106270.
  3. 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.
  4. 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.
  5. 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.
  6. Leng AM, Radmall KS, Shukla PK, Chandrasekharan MB (2022). Quantitative Assessment of Histone H2B Monoubiquitination in Yeast Using Immunoblotting. Methods Protoc, 5(5).
  7. 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.
  8. 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.
  9. Johnson DP, Chandrasekharan MB, Dutreix M, Bhaskara S (2021). Targeting DNA Repair and Chromatin Crosstalk in Cancer Therapy. Cancers (Basel), 13(3).
  10. 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.
  11. 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.
  12. 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.
  13. 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 (2018). 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. Zhou X, Chandrasekharan MB, Hall TC (2004). High rooting frequency and functional analysis of GUS and GFP expression in transgenic Medicago truncatula A17. New Phytol, 162, 813-822.
  36. 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.
  37. Chandrasekharan MB, Bishop KJ, Hall TC (2003). Module-specific regulation of the beta-phaseolin promoter during embryogenesis. Plant J, 33(5), 853-66.
  38. 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.
  39. 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.
  40. 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.
  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.
  3. Li G, Chandrasekharan MB, Wolffe AP, Hall TC (2001). Chromatin structure and phaseolin gene regulation. [Review]. Plant Mol Biol, 46(2), 121-9.
  4. Iyer LM, Kumpatla SP, Chandrasekharan MB, Hall TC (2000). Transgene silencing in monocots. [Review]. Plant Mol Biol, 43(2-3), 323-46.
  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.