by Simone Alves
MLL1 epigenetically regulates postnatal neural specification
New neurons arise in the brain throughout adulthood, but the mechanisms that maintain neurogenesis are poorly understood. By inducing a mutation that decreases the production of neurons in the young adult brain, researchers have recently established an essential role in neurogenesis for the gene-regulating enzyme known as methyltransferase MLL1.
MLL1 is one of a family of chromatin-remodelling factors — that is, proteins that control whether cells' gene-reading machinery can physically access DNA. Researchers led by Arturo Alvarez-Buylla of the University of California, San Francisco, created transgenic mice in which the Mll1 gene is deleted in neural stem cells at specific time in development1. In addition to dramatically lowering post-natal neurogenesis, the absence of Mll1 also prevented normal migration of neuronal precursors causing immature cell types to accumulate in a region known as the subventricular zone. By combining in vivo and in vitro techniques, the group found that Mll1 is not required for generating the non-neuronal glial cells that neural stem cells also create. Nor was Mll1 required for cell survival, and its absence did not affect the cells' ability to proliferate. Cells missing Mll1 were simply unable to differentiate into neural cells. "This suggests that distinct neural lineages may be maintained by specific chromatin-remodelling factors. It is possible that different neuronal subtypes require different chromatin-remodelling genes for differentiation," says first author Daniel Lim, also a professor at the University of California, San Francisco.
The researchers decided to look at how Mll1 might affect genes involved in neural specification and found that one protein, DLX2, was markedly downregulated when Mll1 was absent. DLX2 controls whether cells in the developing brain brain become neurons or the supporting glial cells. By reintroducing DLX2 back into cells that lacked Mll1, the number of cells expressing neuronal markers increased.
"This paper demonstrates that the model of epigenetic control proposed in embryonic stem cells is useful for studying adult stem cell biology," says Lorenz Studer of Memorial Sloan-Kettering Cancer Center in New York, who is developing methods to convert embryonic stem cells into brain cells. In embryonic stem cells, many developmental genes are 'bivalent', with chromatin modifications that allow their rapid activation or repression. Chromatin-remodelling proteins include the gene-repressing Polycomb group and gene-activating Trithorax group, with Mll1 belonging to the latter class. The work from Lim's team shows that Mll1 is required to convert the bivalent, silenced DLX2 chromatin domain into a monovalent, active domain in neural stem cells — a requirement that could go on throughout adult neurogenesis.
Though it is unclear how MLL1 targets particular sites on the genome, of three regulators Lim examined only DLX2 was bivalent. "This is intriguing because it suggests that MLL1 is recruited to specific loci required for neurogenesis and not gliogenesis," Lim says. He thinks that MLL1 and related proteins, such as MLL2, might each be required for different neuronal subtypes.
Both Lorenz and Lim agree that identifying other targets of MLL1 may reveal key developmental factors that can direct stem cell populations to a neuronal lineage, a strategy that could be useful for leading cells to a specific fate in order to treat various neurological diseases. "When neural stem cells are grafted into most regions of the adult brain, they predominantly differentiate into glia," says Studer. "It would be interesting to test whether MLL1 or downstream factors such as DLX2 could overcome this limitation."
Source: Nature