Dr. David Katz, PhD

Assistant Professor, Department of Cell Biology, Emory University, Atlanta, GA 
Title: Epigenetic regulation of cell fate and the implications for behavior and neurodegeneration

March 1st- 10. 30 AM EST, 9.30 AM CST, 7.30 AM PST, 3.30 PM GMT, 9 PM IST 

LAB ONLINE (http://cellbio.emory.edu/lab/katz/index.htm)

Overall, the goal of the laboratory is to study histone modifications in the germline of C. elegans and mouse as a model for understanding basic stem cell biology and the function of chromatin as an epigenetic transcriptional memory.

Recent evidence has suggested that di-methylation of histone H3 on lysine 4 (H3K4me2) is acquired during transcription in all eukaryotes. From this, it has been proposed that this epigenetic modification may provide a transcriptional memory that helps maintain transcriptional patterns from cell to cell during tissue differentiation. During germline development many genes are highly transcribed and acquire H3K4me2 in their chromatin. If this H3K4me2 epigenetic memory were to be propagated to the next generation it could result in the misregulation of gamete- or meiosis-specific genes in the zygote. As a result, we hypothesized that there may be a requirement for extensive reprogramming of H3K4me2 following meiosis to re-establish a developmental ground state and prevent epigenetic baggage from being inappropriately transmitted to the next generation.

The Katz Lab, Summer 2007A good candidate for this putative activity was the H3K4me2 demethylase KDM1 (formerly known as LSD1). In experiments with a C. elegans KDM1 homolog, spr-5, we demonstrated that the loss of this gene results in a germline mortality phenotype in which the incidence of sterility progressively increases across generations. This sterility correlates with the misregulation of spermatogenesis-expressed genes due to the stable accumulation of H3K4me2 at these loci. This accumulation leads to the inappropriate retention of H3K4me2 in the primordial germ cells (PGCs) as well as defective oogenesis and spermatogenesis. From these results, we have concluded that the demethylation of H3K4me2 by KDM1 plays a critical role in the reprogramming of epigenetic memory between generations. These data represent the first evidence that the proper removal of H3K4me2 in the PGCs is essential for germline maintenance, establishing a clear function for an epigenetic modification in a dynamic developmental process. In addition, these data demonstrate for the first time that H3K4me2 can be faithfully transmitted through many cell divisions and act as an epigenetic memory to affect transcription.

To pursue the role of KDM1 further, we have generated mice with germline mutations in KDM1. Progeny from mice that lack maternal KDM1 exhibit significant embryonic and perinatal lethality. These progeny are genotypically normal, suggesting that the defects are due to the stable transmission of inappropriate histone methylation in the embryo. Furthermore, deletion of KDM1 in the mouse testis results in sterility, with loss of the testis stem cell population. Together with the data from C. elegans, these data suggest that KDM1 may be required to restore totipotency after fertilization, as well as to maintain stem cell populations, by preventing the inheritance of H3K4me2 as an epigenetic transcriptional memory. Based on this proposed role in epigenetic reprogramming, we have proposed that KDM1 demethylation may be a key component of the somatic reprogramming that is induced during the generation of IPS cells and in somatic cell nuclear transfer.