Vani Brahmachari


Epigenetics and Developmental Regulation

Prof. Vani Brahmachari joined ACBR in 1998 initially on deputation from Indian Institute of Science. Her research interest is in the area epigenetic regulation in development and disease. In the area of disease epigenetics, they have demonstrated the role of chromatin organization on dynamic mutation leading to Fragile X syndrome, a congenital disease leading to mental retardation. Their work on the effect of triplet repeats, (CTG)non the expression of the gene associate, led them to demonstrate the influence of epigenetic modifications leading to position-effect in gene translocation. They have reported differential DNA methylation in coronary artery disease patients particularly in the context hyperhomocysteinemia. Thus this was linked to deficiency of vitamin B12 and hence the diet. She and her group have subsequently focussed on identifying novel components of the toolkit of epigenetic regulation in the human genome. Using hypothesis-based approach, putative developmental regulators were identified using peptide-identity based in silico approach on the human genome data,They have identified both transacting factors and cis-regulatory elements. The trans-acting factor, INO80, a chromatin remodelling proteins was predicted to be a developmental regulator, having dual function of ATP-dependent chromatin remodelling as well as DNA binding. All the predicted functions were experimentally validated using in vitro assays using expression cloning, human cells in culture and also during development in Drosophila. This work has demonstrated the moon-lighting/dual function of INO80 in humans and in the Drosophila through sequence-specific interaction with chromatin. The interaction of IN80/Ino80 with different proteins of the epigenetic regulatory complex like the PRC1 and 2 (Polycomb proteins) and the activating complexes(Trithorax complexes) demonstrated by different methods indicated the LEGO-set model for combinatorial interactions leading to economy in protein coding genes in achieving higher evolutionary complexity with limited number of protein coding genes.

Recognizing the importance of the sites of interaction of global regulators on DNA, Dr. Vani embarked on a search for potential interaction sites of PcG&Trx complexes on the human genome. The PRE/TRE (Polycomb/Trithorax Response Elements) sequences were not known in the human genome till recently. A novel PRE/TRE sequence, PRE-PIK3C2B was discovered extensively characterized for function and protein-protein interactions. Currently, the long-range interaction of PRE-PIK3C2B and its contribution to nuclear architecture is being analysed.

In the context of the trithorax homologue ALL1 being involved in childhood leukemia, the issue of chromosomal translocation detection in childhood leukemia which is important for course of treatment, was addresed. This work led to the design of a novel approach of using cDNA from bone marrow of patients for translocation detection as well as pharmacogenetic analysis; polymorphism in TPMT gene which impacts the deleterious side effects. TPMT polymorphism is now being analysed routinely in several hospitals.

In the area of mechanisms leading to lack of correlation between genotype and phenotype,they proposed hypothesis to explain incomplete penetrance and variable expressivity that is encountered in human diseases, especially dominant diseases. The SNP mediated differential targeting of microRNA to the mRNA from homologous genes as possible mechanism for lack of phenotype inspite of a dominant mutation in one of the homologues was proposed in a model and subsequently demonstrated in an experimental model. This work was recognized as one of the ten most innovative ideas published in BioEssays that year.

Honours % Awards:
  1. 1. Fellow of the Indian National Science Academy, (FNA) 2015

Ongoing Projects:
  1. 1. Epigenetics in Health and Disease - (EpiHeD): Work package: Molecular basis of genomic imprinting in mealybugs (CSIR, 2012-17) Network Project.

  2. 2. Delineating the mechanism of transcriptional regulation by chromatin remodelling protein, IN080; Identification and characterisation of the protein complexes(DST 2016-19).

  3. 3. Genome-wide mapping of interaction sites of hINO80, a dual function chromatin remodeling protein on the human genome and analysis of its effect on target gene regulation (CSIR-Univ. Interaction: 2013-16).

Selected Recent Publications:
  1. 19.In praise of mealybugs. Vani Brahmachari, Surbhi Kholi and Parul Gulati (2018). J.Genetics. 97(2): 379-389.

  2. 18.Correlation between desiccation stress response and epigenetic modifications of genes in Drosophila melanogaster: an example of environment-epigenome interaction. Sharma, V., Kohli, S., Brahmachari V. (2017). Biochim Biophys Acta. Gene regulatory Mechanisms 8;1860(10):1058-1068. doi: 10.1016/j.bbagrm.2017.08.001. [Epub ahead of print]

  3. 17.Human PRE-PIK3C2B, an intronic cis-element with dual function of activation and repression. Maini J, Ghasemi M, Yandhuri D, Thakur SS, Brahmachari V. Biochim Biophys Acta. 2017 Feb;1860(2):196-204. doi: 10.1016/j.bbagrm.2016.12.003. Epub 2016 Dec 6

  4. 16.Distinguishing between biochemical and cellular function: Are there peptide signatures for cellular function of proteins? Jain S., Bhattacharyya K., Bakshi R., Narang A., Brahmachari V.(2017) Proteins. 2017 Apr;85(4):682-693. doi: 10.1002/prot.25248. Epub 2017

  5. 15.Interaction of the Chromatin Remodeling Protein hINO80 with DNA. Mendiratta S, Bhatia S, Jain S, Kaur T, Brahmachari V. PLoS One. 2016 Jul 18;11(7):e0159370. doi: 10.1371/journal.pone.0159370. eCollection 2016.

  6. 14.In vivo and in silico studies to identify mechanisms associated with Nurr1 modulation following early life exposure to permethrin in rats. Fedeli D, Montani M, Bordoni L, Galeazzi R, Nasuti C, Correia-Sá L, Domingues VF, Jayant M, Brahmachari V, Massaccesi L, Laudadio E, Gabbianelli R. Neuroscience, (2016); 340:411-423. doi: 10.1016/j.neuroscience.2016.10.071. [Epub ahead of print]

  7. 13.The functional diversity of Drosophila Ino80 in development. Ghasemi M, Pawar H, Mishra RK, Brahmachari V (2015) Mech. Dev. 138, 113-121.

  8. 12.Chandolia A, Rathor N, Sharma M, Saini NK, Sinha R, Malhotra P, Brahmachari V, Bose M (2014); Functional analysis of mce4A gene of Mycobacterium tuberculosis H37Rv using antisense approach. Microbiol Res., 169(2014): 780-787.

  9. 11.Sharma, P., Garg, G., Kumar, A., Mohammad, F., Kumar, S.R., Tanwar, V.S., Sati, S., Sharma, A., Karthikeyan, G., Brahmachari# V., Sengupta,# S. (2014); Genome wide DNA Methylation profiling for Epigenetic alteration in Coronary Artery Disease patients. Gene,10; 541(1):31-40.

  10. 10.Hemant Bengani, Shweta Mendiratta ,Jayant Maini, Dasari Vasanthi, Hina Sultana, Mohsen Ghasemi, JasmineAhluwalia, SowmyaRamachandran, Rakesh K Mishra and Vani Brahmachari (2013) Identification and validation of a putative polycomb responsive element in the human genome. PLoS One. 21;8(6):e67217.

  11. 9. Proximity of H2A.Z containing nucleosome to the transcription start site influences gene expression levels in the mammalian liver and brain. Bargaje R, Alam P, Patowary A, Sarkar M, Ali T, Gupta S, Garg M, Singh M, Purkanti R, Scaria V, Sivasubbu S, Brahmachari V, Pillai B. Nucleic Acids Res.(2012) doi: 10.1093/nar/gks665.

  12. 8.Modeling SNP mediated differential targeting of homologous 3'UTR by MicroRNA. Ahluwalia JK, Soni K, Sivasubbu S, Brahmachari V. RNA Biol. 2012 Mar 1; 9(3).

  13. 7.Nucleosomal occupancy and CGG repeat expansion: a comparative analysis of triplet repeat region from mouse and human fragile X mental retardation gene 1.Datta S, Alam MP, Majumdar SS, Mehta AK, Maiti S, Wadhwa N, Brahmachari V.(2011) Chromosome Res. Volume 19, Issue 4, 445-455.

  14. 6.Single nucleotide polymorphism in the genes of mce1 and mce4 operons of Mycobacterium tuberculosis: analysis of clinical isolates and standard reference strains. Pasricha R, Chandolia A, Ponnan P, Saini N.K., Sharma S, Chopra M, Basil M.V., Brahmachari V and Bose M. (2011) BMC Microbiology 2011, 11:41.

  15. 5.Differential serum cytokine levels are associated with cytokine gene polymorphisms in north Indians with active pulmonary tuberculosis. Abhimanyu, Mangangcha IR, Jha P, Arora K, Mukerji M, Banavaliker JN, Indian Genome Variation Consortium, Brahmachari V, Bose M. Infect Genet Evol. 2011 Jul;11(5):1015-22. Epub 2011 Apr 1.

  16. 4.Chromatin remodeling protein INO80 has a role in regulation of homeotic gene expression in Drosophila. Shipra Bhatia, Hema Pawar, Vasanthi Dasari, Rakesh K. Mishra, Shanti Chandrashekaran and Vani Brahmachari (2010), Genes to Cells, 15,725-735.

  17. 3.Comparative analysis of DNA methylation in transgenic mice with unstable CGG repeats from FMR1 gene. Mohammad Parwez Alam, Sonal Datta, Subeer Majumdar, Abhishek K Mehta, Sujatha Baskaran ,Neerja Gulati and Vani Brahmachari (2010) Epigenetics 5:3, 241-248

  18. 2.Functional analysis of an intergenic non-coding sequence within mce1 operon of M.tuberculosis. Monika Joon, Shipra Bhatia, Rashmi Pasricha, Mridula Bose , Vani Brahmachari (2010) BMC Microbiology,10:128.

  19. 1.An analysis of histone modifications in relation to sex specific chromatin organization in the mealybug Maconellicoccus hirsutus. V. Mathur, G. Mendiratta, M. Ganapathi, P. K. Kennady, B. S. Dwarkanath, G. Pande and V. Brahmachari (2010) Cytogen. and Genomics. Cytogenet Genome Res. 2010;129:323-331(DOI:10.1159/00031589.