By Sharon Dent, Ph.D., David Johnson, Ph.D., and Sarah Adai
Chromatin, the intertwined histone proteins and DNA that are packaged into chromosomes, has long been recognized as a gatekeeper to the underlying DNA template.
While chromatin is typically on the receiving end of the cell's intricate signaling pathways - culminating in the regulation of gene expression - evidence is emerging to give chromatin a previously unrecognized role: as a dynamic participant that transmits received signals back to other proteins to effect changes in cellular responses.
This week in the journal Cell, faculty from MD Anderson's Department of Molecular Carcinogenesis and Center for Cancer Epigenetics review a number of recent studies highlighting chromatin's role as both receiver and transmitter of signals in various cell functions.Review authors Sharon Dent, Ph.D. and David Johnson, Ph.D., highlight this growing area of research, which is relevant both for understanding basic cell regulation and for determining how signaling goes awry in diseases such as cancer.
Histone modifications: key players in chromatin signaling
Posttranslational modification of histones is one way that the cell regulates the packing and unpacking of chromatin, which in turn helps to determine whether a gene is activated or repressed.
Multiple modifications (acetylation, methylation, ubquitination, phosphorylation) of multiple histones (5 major families) combined with a multitude of effects on chromatin give rise to a complex "histone code" that signals the transcriptional machinery to turn genes on or off. In recent years, crosstalk has been observed between different histones, giving rise to further complexity in the histone code.
Most of this research was established in yeast cells, but connections between histone ubquitination and histone methylation, for example, also occur in human cells. In fact, mutations in a human protein highly related to the yeast histone methyltransferase Set1, called MLL, are involved in leukemia.
This work raises the possibility that histones can signal to non-histone proteins in human cells, and that deregulation of these events caused by MLL mutations might contribute to leukemia development.
Chromatin as a signal receiver and transmitter
Research by Sharon Dent and colleagues revealed for the first time that histone modifications - instead of being an end-point for transcriptional regulation - can actually relay information to non-histone proteins, and that the role of chromatin in these events is not limited to DNA-templated events like gene activation. In a series of yeast experiments, Dent and colleagues showed that a signal through a histone protein regulates another protein called Dam1, which is involved in the separation of chromosomes during cell division.
Communication between H2B and Dam1 was the first such instance of crosstalk observed between histone and non-histone proteins. The signaling connection between a chromatin change and a non-DNA-templated process such as chromosome separation was also new.The review article highlights additional non-transcriptional signaling events in which chromatin plays a role:
· DNA repair and checkpoint signaling
· Mitotic exit
· Chromosome segregation
New disease targets
Chromatin's new identity as a non-transcriptional signaling agent opens up a plethora of research avenues. The relevance of the yeast work to normal and disease mechanisms in humans needs to be explored. Defining these networks should also provide new strategies and targets for combating diseases that result from disrupted signaling pathways, including cancer.