Modulation of Epigenetic Regulators and Cell Fate Decisions by miRNAs

Figures & data

Figure 1. Mechanisms and preferred targets of miRNAs.

(A) Molecular mechanisms underlying miRNA-dependent inhibition of gene expression. miRNAs are incorporated in Argonaute proteins, which they guide to mRNAs. Through the interactions of Argonaute proteins with various protein complexes, miRNAs induce translational repression, decapping and deadenylation of the target mRNAs. (B) Transcription factors and epigenetic regulators are preferred targets of miRNAs. We calculated the probability of each gene in a specific functional class being targeted by miRNAs and then plotted the cumulative distribution of the probability values for genes in individual functional categories. Briefly, targeting scores for each human gene and every miRNA seed family were obtained by first averaging the TargetScan aggregate probability of conserved targeting (P_CT) scores [33] of all transcripts that are associated with the gene. The probability of a gene to be targeted by at least one miRNA (P_gene) was calculated as: , where P_miR,gene is the probability that the gene is targeted by a specific miRNA miR, calculated as described above. Transcription factors were obtained from the DBD database [157] and epigenetic regulators by extracting genes that were annotated with epigenetic-related gene ontology terms from the AmiGO database [158]. The number of genes in each category is indicated in parentheses. Compared with all genes, epigenetic regulators and transcription factors tend to have higher probabilities of being miRNA targets.

Figure 2. Epigenetic regulators that are targeted by miRNAs.

(A) miRNAs that directly or indirectly regulate targets in the DNA methylation/demethylation pathways. (B–E) miRNAs that target a catalytic subunit of (B) PCR2, (C) PCR1, (D) SWI/SNF complex subunits and (E) histone deacetylases.

Table 1. miRNAs that target epigenetic regulators.

miRNA	Target	Targeting	Ref.
hsa-miR-302	MECP2	3´ UTR	[79]
hsa-miR-148a	DNMT3B	CDS	[75]
mmu-miR-290–295 cluster	Dnmt3a Dnmt3b	Indirect via Rbl2 Indirect via Rbl2	[80,81]
hsa-miR-29a/b/c	DNMT3A DNMT3B	3´ UTR 3´ UTR	[76,77]
hsa-miR-29a	TET1 TET2 TET3	3´ UTR 3´ UTR 3´ UTR	[78]
hsa-miR-29b	DNMT1	Indirect via SP1	[77]
hsa-miR-152 hsa-miR-148a	DNMT1	3´ UTR 3´ UTR	[74]
hsa-miR-302	DNMT1	Indirect via AOF2	[79]
hsa-miR-26a	EZH2	3´ UTR	[103]
hsa-miR-101	EZH2	3´ UTR	[104,105]
mmu-miR-137	Ezh2	3´ UTR	[106]
mmu-miR-214	Ezh2	3´ UTR	[107]
hsa-miR-128	BMI-1	3´ UTR	[102]
mmu-miR-128 mmu-miR-183 mmu-miR-200c mmu-miR-203	Bmi-1	3´ UTR 3´ UTR 3´ UTR 3´ UTR	[101]
mmu-miR-294	Baf170	3´ UTR	[Gruber AJ & Zavolan M, Unpublished Data]
hsa-miR-199a	BRM	3´ UTR	[118]
mmu-miR-9* mmu-miR-124	Baf53a	3´ UTR 3´ UTR	[152]
hsa-miR-449a	HDAC1	3´ UTR	[122]
mmu-miR-1	Hdac4	3´ UTR	[123]
mmu-miR-29b	Hdac4	3´ UTR	[124,126]
mmu-miR-206	Hdac4	3´ UTR	[124,125]
hsa-miR-433	HDAC6	3´ UTR	[127]

CDS: Coding DNA sequence; hsa: Homo sapiens; mmu: Mus musculus ; UTR: Untranslated region.

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