Epigenética: proteína ligada à leucemia 'agenda' genes altamente ativos durante a divisão celular

Epigenetics: Protein Linked to Leukemia 'Bookmarks' Highly Active Genes During Cell Division

ScienceDaily (Jan. 7, 2010) — Each cell inherits genes from its parent as well as epigenetic information -- what amounts to an instruction manual that specifies which genes should be activated or "expressed," when and to what level. Cold Spring Harbor Laboratory (CSHL) scientist Chris Vakoc, M.D., Ph.D., and his team have now discovered how some of these epigenetic instructions get stably transferred from one generation of cells to the next.

The scientists report that newly formed cells inherit the knowledge of which genes need to become highly active right away thanks to a helpful protein that "bookmarks" these genes during the division of their parent cell. Their findings appear in the December 24th issue of Molecular Cell.

The bookmarking protein, called Mixed Lineage Leukemia or MLL, is notorious for triggering leukemia when the gene that encodes it becomes mutated. MLL mutations are among the most common genetic aberrations in leukemia, occurring in about 10% of leukemia cases.

"We now have a clearer picture of what MLL normally does in healthy cells to help gene expression information to travel from parent cells to daughter cells," said Vakoc. "These findings may help us understand how mutated MLL subverts inheritance mechanisms in leukemic cells."

During cell division or "mitosis," all gene activity is temporarily shut down. The dividing cell's chromosomes -- the X-shaped coils of DNA -- condense into tight clumps and expel most proteins that cling to DNA to maintain gene expression.
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Journal Reference:

Molecular Cell
Volume 36, Issue 6, 24 December 2009, Pages 970-983

A Reconfigured Pattern of MLL Occupancy within Mitotic Chromatin Promotes Rapid Transcriptional Reactivation Following Mitotic Exit

Gerd A. Blobel2, Stephan Kadauke2, Eric Wang1, Alan W. Lau3, Johannes Zuber1, Margaret M. Chou3 and Christopher R. Vakoc1, ,

1 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA

2 The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA

3 University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA


Received 8 April 2009; revised 3 August 2009; accepted 3 December 2009. Published: December 24, 2009. Available online 24 December 2009.
Summary

Mixed lineage leukemia (MLL) and its metazoan Trithorax orthologs have been linked with the epigenetic maintenance of transcriptional activity. To identify mechanisms by which MLL perpetuates active transcription in dividing cells, we investigated its role during M phase of the cell cycle. Unlike other chromatin-modifying enzymes examined, we found that MLL associates with gene promoters packaged within condensed mitotic chromosomes. Genome-wide location analysis identified a globally rearranged pattern of MLL occupancy during mitosis in a manner favoring genes that were highly transcribed during interphase. Knockdown experiments revealed that MLL retention at gene promoters during mitosis accelerates transcription reactivation following mitotic exit. MLL tethers Menin, RbBP5, and ASH2L to its occupied sites during mitosis, but is dispensable for preserving histone H3K4 methylation. These findings implicate mitotic bookmarking as a component of Trithorax-based gene regulation, which may facilitate inheritance of active gene expression states during cell division.

Author Keywords: DNA; CELLCYCLE

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