RNA-dependent stabilization of SUV39H1 at constitutive heterochromatin

Autor: Rachel J. O’Neill, Shannon M. McNulty, Whitney L Johnson, Aaron F. Straight, Jason C. Bell, Beth A. Sullivan, Zachary Duda, William T. Yewdell
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: eLife, Vol 6 (2017)
eLife
Popis: Heterochromatin formed by the SUV39 histone methyltransferases represses transcription from repetitive DNA sequences and ensures genomic stability. How SUV39 enzymes localize to their target genomic loci remains unclear. Here, we demonstrate that chromatin-associated RNA contributes to the stable association of SUV39H1 with constitutive heterochromatin in human cells. We find that RNA associated with mitotic chromosomes is concentrated at pericentric heterochromatin, and is encoded, in part, by repetitive α-satellite sequences, which are retained in cis at their transcription sites. Purified SUV39H1 directly binds nucleic acids through its chromodomain; and in cells, SUV39H1 associates with α-satellite RNA transcripts. Furthermore, nucleic acid binding mutants destabilize the association of SUV39H1 with chromatin in mitotic and interphase cells – effects that can be recapitulated by RNase treatment or RNA polymerase inhibition – and cause defects in heterochromatin function. Collectively, our findings uncover a previously unrealized function for chromatin-associated RNA in regulating constitutive heterochromatin in human cells. DOI: http://dx.doi.org/10.7554/eLife.25299.001
eLife digest Each cell in a human body contains the same DNA sequence, which serves as a set of instructions for how the body should develop and operate. However, only certain sections of DNA are “active” at any particular time and in any given type of cell. When a section of DNA is active, cells make many copies of it using a molecule called RNA. When a section of DNA in inactive, very little RNA is made. Some sections of DNA must always be kept inactive to avoid damaging the cell. DNA is packaged around proteins called histones, and enzymes that modify histones control which sections of DNA are switched on or off. One such modifying enzyme, called SUV39H1, is important for inactivating sections of DNA that could cause harm to the cell if they are active. Previous studies showed that the loss of SUV39H1 and related proteins cause abnormalities and cancer in mice. However, it is not clear how this enzyme identifies and inactivates the DNA it needs to target. Johnson, Yewdell et al. studied SUV39H1 in human cells. The experiments show that RNA binds to the SUV39H1 enzyme and controls how it interacts with DNA. Specifically, Johnson, Yewdell et al. found that sections of DNA that are inactive can still make a small amount of RNA, and that this RNA tethers SUV39H1 to the DNA to keep the DNA switched off. Mutant forms of SUV39H1 that are unable to interact with RNA fall off the DNA, which allows DNA sequences that are normally switched off to become active. The findings of Johnson, Yewdell et al. reveal a new role for RNAs in regulating whether DNA is switched on or off. The next step is to determine whether other enzymes that can also modify histones use the same mechanism to activate or inactivate DNA. Differences in how the activity of DNA is regulated between individuals plays a crucial role in generating the diversity we see in nature. Therefore, this work helps us to understand our basic biology and may provide new opportunities for treating disease. DOI: http://dx.doi.org/10.7554/eLife.25299.002
Databáze: OpenAIRE
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