Read our selection of the most exciting Epigenetics research papers published this month.
p53 acts as a powerful tumor suppressor in normal cells. However, certain missense mutations can cause p53 to gain tumorigenic potential. Although there is evidence that gain-of-function (GOF) p53 acts through transcriptional regulation of oncogenic pathways, the individual pathways targeted by GOF p53 have not been established.
To further understand the oncogenic function of p53 GOF, a team led by Shelley Berger from the University of Pennsylvania in Philadelphia investigated the role of chromatin pathways. They found that:
The results of this study reveal that GOF p53 mutations contribute to cell proliferation through chromatin pathways, particularly involving the histone methyltransferase MLL1. This raises the possibility that p53 GOF cancers may be treated using epigenetic therapeutics in the future.
Read the full article in Nature, September 2015.
RNA binding protein HNRNPA2B1 is an m6A reader that regulates miRNA processing
N6-methyladenosine (m6A) is the most common RNA methylation and has been implicated in processes such as miRNA processing. However, a reader of this mark that mediates nuclear RNA processing has not previously been identified.
Claudio Alarcόn and colleagues from Rockefeller University and Columbia University in New York identified the RNA binding protein HNRNPA2B1 as a reader of m6A. They found that:
These results identify HNRNPA2B1 as a nuclear reader of the m6A mark. The data support a model in which HNRNPA2B1 acts downstream of METTL3/m6A to regulate processing of pri-miRNAs.
Read the full paper in Cell, September 2015.
Mel18 is required to specify PRC1 function in a context- and stage-specific manner
Polycomb repressive complexes, PRC1 and PRC2, are important epigenetic regulators in embryonic and adult stem cells. The core subunit composition of the polycomb complexes can vary to regulate distinct biological processes; however, the mechanisms behind this specificity are currently unknown.
By focusing on Mel18, one of six polycomb group RING finger protein (PCGF) paralogues, a team led by Luciano Di Croce from the Centre for Genomic Regulation and Pompeu Fabra University in Barcelona found that:
The data presented in this paper show that Mel18 is required to specify PRC1 function in both a context- and stage-specific manner to maintain proper transcriptional regulation in the early stages of cardiac differentiation.
Read the full paper in Cell Stem Cell, September 2015.
Daxx/Atrx prevent dysfunction of repeat elements in the absence of DNA methylation
A crucial role of DNA methylation is to prevent aberrant transcription and recombination of repeat elements. However, repetitive sequences are also protected during hypomethylation, indicating that alternative mechanisms must also exist.
A team led by Zhou Songyang from Sun Yat-sen University in Guangzhou, China and Baylor College of Medicine in Houston, Texas tested the hypothesis that the Daxx/Atrx complex has a role in protecting repetitive sequences. By studying DNA methyltransferase triple knockout mouse embryonic stem cells (mESCs), they found that:
The data presented in this study demonstrate a role of Atrx and Daxx in preventing repetitive element dysfunction in the absence of DNA methylation. This mechanism is may be essential to safeguard the genome of cell types that display low levels of DNA methylation.
Read the full paper in Cell Stem Cell, September 2015.
Investigating BET inhibitor resistance in leukemia
The following two selected papers have looked at resistance to small molecule inhibitors that target BET proteins including the chromatin reader BRD4. BET inhibitors are promising epigenetic therapies for a range of cancers and are currently being tested in clinical trials in patients with acute myeloid leukemia (AML).
In these two papers, different approaches were taken to investigate the mechanisms behind resistance and sensitivity to BET inhibitors in leukemia cells.
BET inhibitor resistance is conferred through increase in WNT/β-catenin pathway
A team led by Mark Dawson from the Peter MacCallum Cancer Centre and the University of Melbourne, Australia approached this problem by generating cell lines that were resistant the BET inhibitor I-BET. Resistant cell lines were generated by exposing immortalized hematopoetic stem progenitor cells to increasing concentrations of I-BET and selecting resistant cells.
They found that:
In this study, the authors have identified a potential mechanism behind BET resistance in leukemia cells. BET inhibitors are an extremely promising cancer drug and this work will enable future research to develop strategies to eliminate resistant cell populations.
Read the full paper in Nature, September 2015.
WNT signaling is a driver of primary and acquired BET resistance in leukemia
In this research, a team lead by Johannes Zuber from Vienna Biocenter in Austria used a chromatin-focused RNAi screen in AML cells that were sensitive to the BET inhibitor JQ1. By investigating transcriptional profiles in sensitive and resistant leukemias, they found that:
This research implicates WNT activation in driving resistance in leukemia. JQ1 resistant leukemia cells inactivate PRC2 and rewire the transcriptional regulation of BRD4 targets. The BRD4 dependency of MYC is bypassed by activation of the WNT signaling pathway rather than by direct regulation by PRC2 suppression.
Read the full paper in Nature, September 2015.
NK-kB2 regulates EZH2 and prevents senescence
Overexpression of enhancer of Zeste homologue 2 (EZH2) results in altered H3K27 methylation. In cancer, EZH2 has been reported to increase cancer growth and metastasis, and suppress the senescence program. Despite its important role in cancer, EZH2 regulation is not fully understood.
A team led by Thierry Passeron from the Mediterranean Center of Molecular Medicine and the University Hospital of Nice, France sought to further understand regulation of EZH2. By looking at the relationship between NF-kB2 and EZH2 in melanoma metastases, they found that:
The results presented in this study demonstrate the crucial role the non-canonical NF-kB pathway has in regulating EZH2 expression and senescence, and highlight the therapeutic potential of inhibiting this pathway in melanoma.
Read the full paper in Oncogene, September 2015.
Argonaute is essential for correct miRNA strand selection and miRNA ejection
MicroRNAs (miRNAs) are involved in posttranscriptional gene regulation as part of the miRNA induced silencing complex (miRISC). Transcriptional silencing by miRNAs involves association of a guide miRNA with Argonaute protein, while the complementary passenger miRNA strand is discarded.
To understand the protein and miRNA dynamics associated with miRISC maturation, a team led by Victor Ambros from the University of Massachusetts Medical School characterized a previously identified antimorphic mutant of the Argonaute-like protein ALG-1. This mutated protein, in complex with miRNAs, fails to mature into effector miRISCs.
The team found that:
Overall, these results suggest that during miRISC maturation, ALG-1 complexes must recognize structural miRNA features for correct strand selection and miRNA ejection.
Read the full text in PNAS, September 2015.
Find out about recent research into miRNAs as biomarkers for a range of diseases.