Positions

Professor
Molecular and Human Genetics
Baylor College of Medicine
Houston, TX, US
Professor
Molecular Virology and Microbiology
Baylor College of Medicine
Professor
Program in Integrative Molecular and Biomedical Sciences
Baylor College of Medicine
Faculty Senator
Baylor College of Medicine
Houston, Texas, United States
Member
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas, United States

Education

PhD from Universite Libre De Bruxelles
Post-Doctoral Fellowship at Massachusetts Institute Of Technology
Post-Doctoral Fellowship at University Of California, San Francisco

Honors & Awards

Michael E. DeBakey, M.D., Excellence in Research Award

Professional Interests

  • Epigenetic inheritance and phenotypic variability

Professional Statement

Molecular Noise and Epigenetic Inheritance

Phenotypic inheritance relies on the correct transfer of the genetic (DNA) and epigenetic (heritable expression state) information. It is well established that DNA alteration can heritably change the phenotype of a cell, but what is less clear is what triggers heritable epigenetic change. Seminal work in bacteria has highlighted the importance of genetic networks in epigenetic inheritance. To generate stable phenotypic diversity in a population, cells with identical genomes can be differently programmed by transcription factors connected in a positive feedback loop, allowing the stable expression of two alternative phenotypes. Regulatory proteins associated with these molecular switches are often present in low numbers and therefore, subject to fluctuation or "molecular noise". Therefore, the strategy used by a genetic network to control levels of its key regulators is fundamental to the understanding of the potential sources of dysregulation. Molecular noise in gene expression is universal and arises as a result of the stochastic nature of transcription and translation and can directly perturb the behavior of genetic-regulatory-networks generating phenotypic diversity.

My lab is investigating the role of transient errors in information transfer (transcription, translation, or post-translational modification errors) in the dysregulation of bistable genetic networks leading to heritable change in phenotype. To study the contribution of information transfer errors on the generation of heritable phenotypic diversity, we are using classical bistable switches in the bacterium Escherichia coli; the bacteriophage lambda genetic switch; and the Lac operon.

With the exception of Prion inheritance, the idea that transient errors in information transfer from RNA to protein can have heritable consequences without any alteration of the DNA sequence has not been considered before, but our work challenge this idea by showing that transient alteration of autocatalytic systems can have profound heritable consequences. Thus, our work suggests that transient errors in information transfer may be an important mechanism of epigenetic change and should be considered as the causative agent for many human diseases ranging from the progression of AIDS to devastating neurodegenerative diseases.

Selected Publications

Funding

Molecular Noise, Transcription Errors and Heritable Phenotypic Change
- #R01GM088653
Grant funding from NIH
The overall goal of this research is to define the origins and the consequences of errors in information transfer from DNA to protein in the perpetuation and perturbation of genetic regulatory networks that generate stable phenotypes in cellular lineages of Escherichia coli, e.g. bistable switches. Bistability has been proposed as a mechanism for decision-making and memory in gene circuits, relying on positive feedback loops between transcription factors of low abundance. The central hypothesis of this proposal is that transient errors in the information transfer from DNA to protein contribute to protein fluctuation (molecular noise) and that these errors can cause heritable non-genetic phenotypic heterogeneity, when associated with bistable regulatory networks. Specifically, we propose that the transient disappearance of functional protein (in our case, a repressor that negatively regulates the expression of other genes) due to errors in transcription, translation, or protein folding can produce a heritable phenotypic change in genetically identical cells growing in the same environment. To capture and quantify transient events from such errors, two well characterized bistable systems will be used, the lactose operon and the lambda switch. In these systems, the stochastic switching from one phenotypic state to the alternative phenotypic state will be an indicator of molecular noise. This work will illuminate the fundamental cell/molecular biology of protein-based epigenetic switches, which are likely to be critical to many fundamental aspects of biology and medicine including cancer, aging, prion genesis, and pluripotency of stem cells.
Public Health Relevance
To generate diversity, cells run specific programs orchestrated by specific protein regulators. Sometimes the making of these proteins is erroneous, leading to dysfunction of the program, and loss of cellular identity. Our study aims to understand the origin and consequence of these errors on these protein regulators.