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本帖最后由 saturn 于 2010-5-12 18:12 编辑 k. d# r$ D. g$ O" s. o
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here are several publications elucidate miRNA is an epigenetic regulator
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Review) G1 L( C8 x) V: @) s2 V- f% V& D
Epigenetic mechanisms in glioblastoma multiforme
1 ?, [6 e& _, d% D6 Z: GRaman P. Nagarajana and Joseph F. CostelloCorresponding Author Contact Information, a, E-mail The Corresponding Author. o0 |- K, h1 i& m) G& ^0 D; v& |
aBrain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA
4 |, f# }- Y3 QAvailable online 20 February 2009.( H9 Y p/ P, V$ j% \3 ~# e: _8 i
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2.7. Aberrant expression of microRNAs in GBM
1 n$ b! N% d" m& YMicroRNAs (miRNAs), non-coding RNAs which are potential epigenetic regulatory effectors, are important in normal mammalian development and dysregulation of their expression has been observed in multiple human cancers. MiRNAs are 19–25 nt in length and are cleaved from 60–110 nt hairpin precursors (pre-miRNAs) derived from larger primary transcripts (pri-miRNAs). MiRNAs can regulate gene expression through interactions with mRNAs in regions of sequence complementary, blocking translation of mRNAs [103].
6 Q9 M+ f1 [4 g. y7 m2 o5 eIn GBM, multiple miRNAs are aberrantly expressed or repressed in both primary tumors and cell lines [104]. Primary GBMs and cell lines overexpress miR-221, whereas a set of brain-enriched miRNAs (miR-128, miR-181a, miR-181b, and miR-181c) shows decreased expression [105]. Reduced miR-128 expression in GBM and consequent reduced cell proliferation in vitro and in xenografts [106] were shown in a separate study. Furthermore, miR-128 regulates the expression of the polycomb complex protein Bmi-1 through binding at the BMI-1 3′-UTR, resulting in decreased Bmi-1 and H3K27me3 levels. In GBM-derived neurosphere cells, miR-128 overexpression blocked stem cell self-renewal, indicating that miR-128 can regulate the stem cell-like capabilities of a subset of GBM cells.
" [/ m7 W, [: D5 |) B2 M4 ?Additional microRNAs are aberrantly expressed in GBM. MiR-124 and miR-137 are underexpressed in primary GBM and anaplastic astrocytoma [107]. MiR-137 expression was increased in GBM cell lines U87 and U251 following treatment with 5-aza-2′-deoxycytidine, suggesting regulation of these microRNAs by DNA methylation. Functionally, miR-124 and miR-137 inhibit proliferation in GBM and can induce differentiation of normal neural and brain tumor stem cells. Additional studies have demonstrated that miR-124 is underexpressed in primary oligodendrogliomas, astroblastomas, and GBM cell lines [108], [109] and [110] indicating a potentially central role for this non-coding RNA in brain tumors. Overall, microRNAs appear to play multiple roles in cancer biology; for example in GBM miR-21 has both anti-apoptotic and pro-invasion functions
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REVIEW
* ]( v+ N% g7 P( i! r6 WThe microRNA network and tumor metastasis3 S/ E( h( q2 w" _: @& g* l7 _
H Zhang, Y Li and M Lai2 L* n3 t3 k) |9 N% s
Department of Pathology, School of Medicine, Zhejiang University, Zhejiang, PR China
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4 U6 N7 t" X5 v. Q' d, QThe reciprocal regulation between miRNA and epigenetic modification in tumor metastasis
4 C: Y+ O! V. |4 w: G( B, g7 w. OEpigenetic modifications include DNA methylation and covalent modification of histones. These alterations are reversible, but very stable, and have a significant impact on the regulation of gene expression, the contribution of which to cancer goes beyond the early stages of tumor transformation to affect metastasis. However, miRNAs have an important role in epigenetic modification, and are also regulated by epigenetic mechanisms in tumor metastasis.
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) l; t+ o* z; u7 zNature Reviews Rheumatology 5, 266-272 (May 2009) | doi:10.1038/nrrheum.2009.55
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Epigenetic control in rheumatoid arthritis synovial fibroblasts' |! h. f$ q; ]- S+ a
2 u; g8 a1 p' }, |+ @7 n0 `3 E eEmmanuel Karouzakis, Renate E. Gay, Steffen Gay & Michel Neidhart
# B v/ g9 b9 ^ D8 yAbstract
0 y+ }2 x% Q/ V2 cRheumatoid arthritis synovial fibroblasts (RASFs) are the effector cells of cartilage and bone destruction. These cells show an 'intrinsically' activated and aggressive phenotype that results in the increased production of matrix-degrading enzymes and adhesion molecules, and is conserved over long-term passage in vitro. The three main mechanisms of epigenetic control—DNA methylation, histone modifications and microRNA activity—interact in the development of the RASF phenotype. The extent of global DNA methylation is reduced in synoviocytes in situ and RASFs in vitro. In addition, histone hyperacetylation occurs and specific microRNAs are expressed in RASFs. Normal synovial fibroblasts cultured in a hypomethylating milieu acquire an activated phenotype similar to that of RASFs. These findings suggest that epigenetic control, in particular the control of DNA methylation, is deficient in RASFs. Genome-wide analyses of the epigenome will enable the detection of additional genes involved in the pathogenesis of rheumatoid arthritis, the identification of epigenetic biomarkers, and potentially the development of a therapeutic regimen that targets activated RASFs.
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Leukaemogenesis:more than mutant genes6 s. W' t* v8 |- ?, I0 N
Jianjun Chen*§, Olatoyosi Odenike*§ and Janet D. Rowley*‡% ?( L/ F K0 I- ]" i
Abstract | Acute leukaemias are characterized by recurring chromosomal aberrations andgene mutations that are crucial to disease pathogenesis. It is now evident that epigenetic modifications, including DNA methylation and histone modifications, substantially contribute to the phenotype of leukaemia cells. An additional layer of epigenetic complexity is the pathogenetic role of microRNAs in leukaemias, and their key role in the transcriptional regulation of tumour suppressor genes and oncogenes. The genetic heterogeneity of acute leukaemias poses therapeutic challenges, but pharmacological agents that target components of the epigenetic machinery are promising as a component of the therapeutic arsenal for this group of diseases.
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$ w; _& l2 Q3 S1 fhope for your comments, by the way could you list some evidences show that miRNA is not an epigenetic effector?(from the expert you mentioned) |
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发表于 2010-5-12 13:12
发表于 2010-5-13 07:05
，网坛嘛，要是同你在论坛或杂志上pk的话那才叫本事。6 Z) n5 _; G4 k; _