Tuesday, November 9, 2010

Thanks for the Histones, Mom!

Several papers have emerged over the last year or so indicating transgenerational effects that influence the behavior and/or physiology of offspring. For example, a recent study in Nature from Margaret Morris's group at the University of New South Wales proposes that obese father's transmit an epigenetic signature through the germ line to female offspring, resulting in impaired beta cell function, impaired insulin secretion and glucose intolerance (Ng et al. Nature 2010). Other recent studies have found similar evidence for paternal inheritance of non-genetic information (for example, see Pentinat et al. Endocrinology 2010; Nelson et al. Epigenomics 2010). However, an outstanding issue relates to the identity of the underlying molecular mechanisms that are involved in these effects. In this blog entry, I highlight some emerging pathways that might potentially contribute to epigenetic inheritance through the germ line.

Two major studies have characterized modified histones in human and mouse sperm (Hammoud et al. Nature 2009; Brykczynska et al. Nat Struc Mol Biol 2010). Previously, it was thought that modified histones were unlikely to be a major component of the highly compact chromatin contained in sperm. However, these two studies indicate that approximately 30% of human promoters contain modified histones. Further, many of these epigenetic signatures are conserved between humans and mice. It has been postulated that these histone signatures are retained in the zygote and play an important role at early stages of development in offspring. However, direct evidence for this model is not yet strong. Interestingly, two noteworthy studies in C. elegans suggest that modified histones established in the parental germ cells transmit essential information to offspring through the germ line (Furuhashi et al. Epigenetics 2010; Rechtsteiner et al. PLoS Genetics 2010).

Both of these studies pickup on an older study by Susan Strome's group, in which she found 6 loci, including the H3K36 methyltransferase MES–4 [an NSD homolog], that are required for normal germ cell development in offspring (Capowski et al. Genetics 1991). Null MES-4 mutant offspring undergo normal germ cell development when MES–4 is expressed by the mother, but not if the mother is homozygous. Thus, a transgenerational maternal effect occurs. In the two most recent studies, it was found that MES–4 establishes H3K36 trimethylated histone marks independent of transcription, and this maternally established epigenetic signature is required for normal germ cell development in offspring. The authors propose that MES–4 transmits a memory of gene expression in the parental germline to offspring.

Taken together, these early observations suggest that epigenetic signatures in the form of modified histones in eggs and/or sperm might impact upon gene expression and the development and physiology of offspring.

Monday, November 8, 2010

Eppendorf & Science Prize for Neurobiology

Thank you to everyone sending congratulatory messages regarding the Eppendorf & Science Prize.  A link to my essay is provided here:

Parental Control Over the Brain

This work is the result a major collaborative effort.  Jiangwen Zhang at Harvard FAS Computing played a central role in the development of the informatics pipeline.  While next generation sequencing data analysis is becoming more mainstream, there was absolutely nothing to help in early 2007 (beyond Eland and a few other aligners) when we started and Jiangwen's work was essential to getting it up and running.  David Haig at Harvard played a vital role in the development of the statistical analysis and data interpretation.  Gary Schroth and Shujun Luo at Illumina kindly collaborated by sharing their early versions of an RNA-Seq protocol and by carrying out some pilot sequencing studies for us to determine if the approach would succeed (yes, the initiation of the study predated publication of RNA-Seq).  Jim Butler worked on the qPCR analysis of Il18 heterozygous mice.  The entire study was carried out under the guidance and mentorship of Catherine Dulac in her lab in the Molecular and Cellular Biology Department at Harvard.

Also, thank you to the Jaenisch lab for sharing mice and the outstanding members of the Dulac lab for discussions and ideas.

The work was funded by the Klarman Family Foundation for Eating Disorders, the Howard Hughes Medical Institute, and an award from Merck.  I was funded by the Human Frontiers Science Program and the Alberta Heritage Foundation for Medical Research.

Thank you to the Canadian Press for highlighting the prize at home!