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ESI Special Topic: Gene Silencing
Publication Date: December 2006

Gene Silencing

ESI Special Topics: January 2007
Citing URL: http://esi-topics.com/genesil2006/interviews/UtpalBhadra.html

An INTERVIEW with Dr. Utpal Bhadra
This month, Special Topics talks with Dr. Utpal Bhadra about the paper, "Heterochromatic silencing and the HP1 localization in Drosophila are dependent on the RNAi machinery," (Pal-bhadra M, et al., Science 303:669-72, 2004). This paper ranks at #11 among papers on gene silencing published over the past two years, with 155 cites. Dr. Bhadra heads the Functional Genomics and Gene Silencing Group at the Center for Cellular and Molecular Biology (CCMB) in Hyderabad, India.

ST:  Please tell us a little about your educational background and early research.

I obtained my M.Sc. and Ph.D. in Advanced Cytogenetics from the University of Calcutta, India. I received the Young Scientist Award in 1991 and also the Nehru Centenary British Fellowship to continue my doctoral work in the UK. After my Ph.D. I joined as a postdoctoral Research Fellow in the Department of Biology at Harvard University, and later moved to the University of Missouri in Columbia. I got an independent position in Missouri after one year.


Our study demonstrated that RNA interference machinery plays a role in heterochromatin silencing in higher eukaryotes, such as Drosophila, as reported earlier in S. pombe.

I joined CCMB, India, as a Senior Scientist in 2002 and was promoted as a Group Leader within a year. I have been recently selected as an International Fellow of the Wellcome Trust organization from the UK and a top Young Investigator from the Human Frontier Science Program. I have also been selected as a Fellow of UNESCO and the Australian Expert Group of Industrial Study (AEGIS) and a Fellow of National Academy of Science (FNASc) here in India.

Identification and characterization of several transacting dose-dependent regulators targeting white eye color genes in flies was the main focus of my Ph.D. work. I analyzed their specific roles in sex determination and dosage compensation, a natural phenomenon for epigenetic genome control. We identified that the transacting dosage effect, which is the basis for aneuploid syndrome, has a tremendous impact on hyperactivation of male X chromosome. The in-depth studies showed that the Male Specific Lethal (MSL) proteins, which are thought to control dosage compensation by painting the male X chromosome, have negligible effect on hyperactivation of X-linked genes. In reality, they modulate the transacting inverse dosage effects, which has a global impact on the genome regulation and becomes proactive by the loss of one X chromosome in the male.

During my stay at the University of Missouri, we accidentally identified a phenomenon—Co-suppression, the strategy by which plants often silence the expression of multiple transgenes or foreign DNA or transposon activity when they are inserted in different chromosomal locations. Our experiment in flies using w-Adh hybrid transgenes appears to be a first case of co-suppression in animal species. Later, we extended this phenomenon on other hybrid genes to determine its generality.

We also found a case in which w promoter-Adh reduced the expression of reciprocal constructs Adh-w intensively using endogenous Adh as a mediator. We referred to this strategy as "non-homologous co-suppression." An experiment on multiple Adh full-length transgenes revealed that silencing occurs at post-transcriptional level by a sequence-specific RNA degradation process that shares the hallmarks of RNA interference (RNAi), a powerful tool for functional genomics. In the last three years, milestone contributions of RNAi machinery regarding heterochromatin silencing, chromatin dynamics, and nuclear organization have been elucidated from our works.

ST:  How did you become involved in gene silencing research in particular?

To determine the effect of different trans-acting dosage modifiers and map their interacting sequence at the white promoter, we used several transgenic lines carrying w-Adh transgene in different genomic locations. In our study for ADH enzyme expression relative to the amount of gene dosage, unexpectedly, we found that the amount of ADH enzyme was significantly reduced inversely by the number of w-Adh copies in the same fly. This accidental discovery later came to be known as the first case of gene silencing in animals—basically, we brought gene silencing to the animal system.

ST:  Your 2004 Science paper, "Heterochromatic silencing and the HP1 localization in Drosophila are dependent on the RNAi machinery," has been singled out as a highly cited recent paper on gene silencing. Would you please sum up this paper and its significance for the field?

Many active or inducible genes, resident of euchromatin domains, are often silenced by the influence of adjacent condensed chromatin commonly known as heterochromatin. The process is exemplified by the variegated expression in Drosophila genes. Heterochromatin in pericentric regions is likely associated with major modifications of chromatin organization and histone tail modifications, including histone deacetylation, methylation, which concomitantly recruits heterochromatin proteins (HP1 and HP2).

Our study demonstrated that RNA interference machinery plays a role in heterochromatin silencing in higher eukaryotes, such as Drosophila, as reported earlier in S. pombe. Indeed, a few members of RNAi machinery dramatically reduce H3 mK9 and delocalize HP1 and HP2 binding. We hypothesized that small interfering RNA (siRNA), perhaps derived from repetitive DNA, might be embedded in a "Target complex" for directing the condensation process of heterochromatin. The results elucidated the RNAi/heterochromatin pathway, providing new insights into mechanisms of gene silencing, a critical process in development, relevant to many health hazards, including cancer.

ST:  Do you have plans to investigate heterochromatic silencing in other species?

Yes, we have been working on heterochromatin silencing and X chromosomal inactivation and genomic imprinting in mouse and human culture cells.

ST:  If you are free to discuss them, please tell us about your current projects.

Currently these are the following areas in which we are working:

  1. Isolation of a complete set of RNAi components in the fly using genome-wide screening and characterization of some of them to determine their role on RNAi machinery in the nucleus or in the cytosol.
  2. An interrelationship between TGS and PTGS in Drosophila
  3. Transgene-dependent Non-Mendelian inheritance
  4. A link between RNAi, noncoding RNA, and dosage compensation in Drosophila.
  5. Viral resistance and RNAi in Drosophila and humans.End

Dr. Utpal Bhadra
Functional Genomics and Gene Silencing Group
Center for Cellular and Molecular Biology
Hyderabad, India
   

ESI Special Topics: January 2007
Citing URL: http://esi-topics.com/genesil2006/interviews/UtpalBhadra.html

This special topic of Gene Silencing was originally featured in ESI Topics in December 2003. To view the archived Gene Silencing topic, click here.

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