Alternative titles; symbols
HGNC Approved Gene Symbol: MIR29B1
Cytogenetic location: 7q32.3 Genomic coordinates (GRCh38) : 7:130,877,459-130,877,539 (from NCBI)
MicroRNAs (miRNAs) are noncoding RNAs of about 19 to 25 nucleotides that are cleaved from 70- to 100-nucleotide hairpin pre-miRNA precursors. Through partial sequence homology, miRNAs bind to the 3-prime UTRs of target mRNAs, causing a block of translation or, less frequently, mRNA degradation. Two distinct genes, MIR29B1 and MIR29B2 (619035), produce different pre-miRNAs that encode the same mature MIR29B sequence. MIR29B1 is cotranscribed with MIR29A (610782) on chromosome 7q32, and MIR29B2 is cotranscribed with MIR29C (610784) on chromosome 1q32 (Hwang et al., 2007; Sampath et al., 2012).
Using RT-PCR and Northern blot analyses, Hwang et al. (2007) determined that the MIR29B1/MIR29A cluster, but not the MIR29B2/MIR29C cluster, was expressed in HeLa cells. MIR29B was expressed at low levels except in mitotic HeLa cells, MIR29A was constitutively expressed in all HeLa cell cycle phases, and MIR29C was not detectable in HeLa cells. Hwang et al. (2007) found that MIR29B, in contrast to other studied animal miRNAs, localized predominantly to the nucleus in HeLa and NIH3T3 cells. The distinctive hexanucleotide terminal motif of MIR29B, AGUGUU, acted as a transferable nuclear localization element that directed nuclear enrichment of miRNAs or small interfering RNAs to which it was attached. Hwang et al. (2007) concluded that miRNAs sharing common 5-prime sequences, considered to be largely redundant, might have distinct functions because of the influence of cis-acting regulatory motifs. Hwang et al. (2007) found that MIR29B underwent rapid decay, but that accelerated turnover did not appear to be a general feature of small RNAs imported into the nucleus.
Using quantitative RT-PCR, Xu et al. (2009) found that miR29A, miR29B, and miR29C were highly expressed in normal tissues. However, all 3 miR29 isoforms were downregulated in a broad spectrum of solid tumors, including neuroblastoma, sarcomas, brain tumors, and tumor cell lines.
Jiao et al. (2010) reported that MIR29B is highly conserved in vertebrates, with 100% nucleotide identity shared among several species, including human, rodents, and zebrafish. They stated that MIR29B is highly expressed in adult brain and in postmitotic neurons.
Hwang et al. (2007) stated that the MIR29B1/MIR29A gene cluster maps to chromosome 7q32.3.
Branched chain amino acids (BCAAs) play critical roles in cell and tissue functions in addition to being important components of protein structure. Mersey et al. (2005) demonstrated that MIRN29B1 is targeted to the mRNA for the dihydrolipoamide branched-chain acyltransferase component (DBT; 248610) of branched chain-ketoacid dehydrogenase (BCKD) and prevents translation when bound in HEK293 cells. This was the first demonstration of the use of a microRNA to exert control on a metabolic pathway of amino acid catabolism in mammals, and offers an explanation for the observed differences in the amount of the BCKD complex present in different tissues and under varying nutritional states.
MIRN29A, MIRN29B, and MIRN29C are downregulated in lung cancer. Fabbri et al. (2007) identified complementarity sites for the MIRN29s in the 3-prime UTRs of DNMT3A (602769) and DNMT3B (602900), key enzymes involved in DNA methylation that are frequently upregulated in lung cancers with poor prognosis. Expression of the MIRN29s was inversely correlated with levels of DNMT3A and DNMT3B in lung cancer tissues, and the MIRN29s directly targeted DNMT3A and DNMT3B. Enforced expression of MIRN29s in lung cancer cell lines restored normal patterns of DNA methylation, induced reexpression of methylation-silenced tumor suppressor genes, and inhibited tumorigenicity in vitro and in vivo.
Mott et al. (2007) found that the antiapoptotic protein MCL1 (159552) was overexpressed and that miR29B was underexpressed in the malignant human cholangiocarcinoma cell line KMCH compared with normal human cholangiocytes. In silico analysis revealed a putative miR29-binding site in the 3-prime UTR of MCL1 mRNA. Enforced expression of miR29B through transfection of the miR29B1 precursor reduced MCL1 protein expression in KMCH cells. This effect was direct, as miR29B negatively regulated expression of an MCL1 3-prime UTR-based reporter construct. Enforced miR29B expression also sensitized cancer cells to TRAIL (TNFSF10; 603598)-mediated apoptotic cell death. Transfection of nonmalignant cells with an miR29B antagonist increased MCL1 levels and reduced TRAIL-mediated apoptosis. Mott et al. (2007) concluded that miR29 is an endogenous regulator of MCL1 protein expression and apoptosis.
Using microarray and Northern blot analysis, Chang et al. (2008) showed that MIRN29B1 was among several miRNAs downregulated by MYC (190080) in mouse and human B-cell lymphoma cell lines. MYC bound the MIRN29B1 upstream region.
BACE1 (604252) is the beta-secretase that degrades amyloid precursor protein (APP; 104760) into amyloid-beta peptides that show pathogenic accumulation in Alzheimer disease (AD; 104300). Hebert et al. (2008) found that expression of BACE1 protein, but not mRNA, was increased in about 30% of sporadic AD patients, and that expression of the miR29A/miR29B1 cluster was significantly decreased concomitant with high BACE1 protein levels. A similar inverse correlation between Bace1 protein and miR29a/miR29b1 levels was also detected in developing and adult mouse brain and in primary neuronal cultures. Gain- and loss-of-function experiments in human embryonic kidney cells showed that both miR29A and miR29B1 downregulated endogenous BACE1 upon transient overexpression and that the level of APP fragments generated by BACE1 activity decreased following miR29A and miR29B1 expression. Hebert et al. (2008) proposed that loss of specific miRNAs can contribute to increased BACE1 and amyloid-beta levels in sporadic AD.
Using Western blot, quantitative RT-PCR, and FACS analyses, Xu et al. (2009) found that B7H3 (CD276; 605715) transcript was ubiquitously expressed in human normal tissues and solid tumors, but that B7H3 protein was preferentially expressed only in tumor tissues and cell lines. Xu et al. (2009) identified an miR29 target site in the 3-prime UTR of B7H3. All 3 miR29 isoforms share the same seed complementarity to the B7H3 3-prime UTR, suggesting that they all target B7H3. Overall, there was an inverse correlation between B7H3 protein and miR29 expression levels. Luciferase reporter analysis showed that miR29A directly targeted the 3-prime UTR of B7H3. Knockin and knockdown of miR29A led to downregulation and upregulation, respectively, of B7H3 protein expression. Xu et al. (2009) proposed that the ability of miR29 to control B7H3 protein expression has implications for immune escape by solid tumors and may have therapeutic potential.
Garzon et al. (2009) provided evidence supporting a tumor suppressor role for miR29A and miR29B in acute myeloid leukemia (AML; 601626). Overexpression of both microRNAs reduced cell growth and induced apoptosis in AML cell lines. Injection of miR29B in a xenograft mouse model of AML resulted in tumor shrinkage. Northern blot analysis showed that the 2 microRNAs targeted genes involved in apoptosis, the cell cycle, and cell proliferation. Transfection of leukemic cells with miR29A and miR29B resulted in specific downregulation of CXXC6 (TET1; 607790), MCL1 (159552), and CDK6 (603368). Studies of 45 samples from patients with AML showed an inverse correlation between MCL1 and miR29B. Although 42% of the miR29A-correlated genes were also correlated with miR29B, there were some differences: genes related to protein metabolism were found overrepresented in miR29B-correlated genes, and genes related to immune function were overrepresented in miR29A-correlated genes. Finally, there was a downregulation of both miR29A and miR29B in primary AML samples with monosomy 7 (252270).
Using gene microarray analysis, Luna et al. (2009) showed that expression of MIR29B in human trabecular meshwork (HTM) cells significantly affected 3 canonical pathways: cell adhesion-extracellular matrix (ECM) remodeling, cytoskeleton remodeling, and cell adhesion-integrin-mediated cell adhesion and migration. Expression of MIR29B downregulated expression of BMP1 (112264), ADAM12 (602714), and NKIRAS2 (604497) by interacting with the 3-prime UTRs of their transcripts. Chronic oxidative stress induced downregulation of MIR29B in HTM cells, which was associated with increased expression of ECM genes regulated by MIR29B. Increased expression of these genes in HTM cells was inhibited by transfection with MIR29B. In addition, HTM cells transfected with MIR29B showed a significant decrease in cytotoxicity compared with controls.
Jiao et al. (2010) noted that expression of MIR29B overlaps with that of progranulin (GRN; 138945). They found that MIR29B suppressed production and secretion of human progranulin by binding directly to the 3-prime UTR of progranulin mRNA.
By screening an miRNA library, Fort et al. (2010) identified the 3 MIR29 family members among a small group of miRNAs that reduced production of fibrinogen (see FGA; 134820) in HuH7 human hepatoma cells. Overexpression of MIR29A, MIR29B, or MIR29C decreased the steady-state levels of all transcripts encoded by the 3 fibrinogen genes in HuH7 cells. Luciferase assays showed that MIR29C specifically lowered FGA-alpha(E) mRNA levels via a target site in the FGA-alpha(E) mRNA 3-prime UTR region. However, MIR29A, MIR29B, and MIR29C appeared to lower all other fibrinogen transcript levels via an indirect mechanism.
Using in silico analysis, Smith et al. (2012) identified both TBET (TBX21; 604895) and IFNG (147570) as targets of MIR29B, suggesting that MIR29B is likely to play an important role in Th1 inflammation. Luciferase analysis confirmed that MIR29B interacted directly with the 3-prime UTRs of human TBET and IFNG and repressed expression. MIR29A also repressed TBET. Mir29b expression was significantly elevated in mice with experimental autoimmune encephalomyelitis (EAE). T-cell production of Ifng was increased 6-fold in mice lacking the Mir29a/Mir29b1 gene cluster (Mir29ab1), and these mice also had enhanced Tbet expression. Mice lacking Mir29ab1 were protected from EAE. Memory T cells from patients with multiple sclerosis (MS; 126200) had significantly increased levels of MIR29B, as well as elevated TBET, although IFNG levels were unchanged. High levels of MIR29B decreased significantly upon T-cell activation in MS patients, suggesting that the feedback loop is dysregulated in MS patients and may contribute to chronic inflammation. Smith et al. (2012) concluded that MIR29 is a regulator of Th1 differentiation and provides a mechanism to balance protective immunity and autoimmunity.
Using RT-PCR analysis, Sampath et al. (2012) showed that histone deacetylases (HDACs) were overexpressed in chronic lymphocytic leukemia (CLL; 151400) and mediated epigenetic silencing of MIR15A (609703), MIR16 (see 609704), and MIR29B. HDAC inhibition resulted in robust accumulation of trimethylated lys4 on histone H3 (see 602810) and restored expression of MIR15A, MIR16, and MIR29B. Ectopic expression of MIR15A and MIR16 or HDAC inhibition-induced expression of MIR15A, MIR16, or MIR29B in primary CLL cells reduced levels of MCL1 (159552), but not BCL2 (151430), and was associated with mitochondrial membrane depolarization and apoptosis.
Brain et al. (2013) detected upregulated expression of MIR29A, MIR29B, and MIR29C in human dendritic cells (DCs) stimulated with NOD2 (605956). They found that MIR29 regulated expression of multiple immune mediators. Notably, MIR29 downregulated IL23 by targeting its IL12p40 (IL23B; 161561) component directly and its IL23p19 (IL23A; 605580) component indirectly, most likely through a reduction of the transcription factor ATF2 (123811). Dextran sodium sulfate (DSS)-induced colitis was exacerbated in mice lacking Mir29 and was associated with elevated Il23 and Th17 cytokines in intestinal mucosa. DCs from Crohn disease (266600) patients expressing NOD2 polymorphisms failed to induce MIR29 after stimulation of pathogen pattern recognition receptors, and these DCs showed enhanced release of IL12p40 on exposure to adherent E. coli. Brain et al. (2013) proposed that loss of MIR29-mediated immune regulation in Crohn disease DCs may contribute to elevated IL23 in patients with the disease.
Zhang et al. (2019) found that high expression of BMP1 promoted osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (BMSCs). In BMSCs, BMP1 expression was negatively regulated by MIR29B-3p. The long noncoding RNA (lncRNA) NEAT1 (612769) upregulated BMP1 expression by binding to MIR29B-3p.
Brain, O., Owens, B. M. J., Pichulik, T., Allan, P., Khatamzas, E., Leslie, A., Steevels, T., Sharma, S., Mayer, A., Catuneanu, A. M., Morton, V., Sun, M.-Y., Jewell, D., Coccia, M., Harrison, O., Maloy, K., Schonefeldt, S., Bornschein, S., Liston, A., Simmons, A. The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. Immunity 39: 521-536, 2013. [PubMed: 24054330] [Full Text: https://doi.org/10.1016/j.immuni.2013.08.035]
Chang, T.-C., Yu, D., Lee, Y.-S., Wentzel, E. A., Arking, D. E., West, K. M., Dang, C. V., Thomas-Tikhonenko, A., Mendell, J. T. Widespread microRNA repression by Myc contributes to tumorigenesis. Nature Genet. 40: 43-50, 2008. [PubMed: 18066065] [Full Text: https://doi.org/10.1038/ng.2007.30]
Fabbri, M., Garzon, R., Cimmino, A., Liu, Z., Zanesi, N., Callegari, E., Liu, S., Alder, H., Costinean, S., Fernandez-Cymering, C., Volinia, S., Guler, G., Morrison, C. D., Chan, K. K., Marcucci, G., Calin, G. A., Huebner, K., Croce, C. M. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc. Nat. Acad. Sci. 104: 15805-15810, 2007. [PubMed: 17890317] [Full Text: https://doi.org/10.1073/pnas.0707628104]
Fort, A., Borel, C., Migliavacca, E., Antonarakis, S. E., Fish, R. J., Neerman-Arbez, M. Regulation of fibrinogen production by microRNAs. Blood 116: 2608-2615, 2010. [PubMed: 20570858] [Full Text: https://doi.org/10.1182/blood-2010-02-268011]
Garzon, R., Heaphy, C. E. A., Havelange, V., Fabbri, M., Volinia, S., Tsao, T., Zanesi, N., Kornblau, S. M., Marcucci, G., Calin, G. A., Andreeff, M., Croce, C. M. MicroRNA 29b functions in acute myeloid leukemia. Blood 114: 5331-5341, 2009. [PubMed: 19850741] [Full Text: https://doi.org/10.1182/blood-2009-03-211938]
Hebert, S. S., Horre, K., Nicolai, L., Papadopoulou, A. S., Mandemakers, W., Silahtaroglu, A. N., Kauppinen, S., Delacourte, A., De Strooper, B. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc. Nat. Acad. Sci. 105: 6415-6420, 2008. [PubMed: 18434550] [Full Text: https://doi.org/10.1073/pnas.0710263105]
Hwang, H.-W., Wentzel, E. A., Mendell, J. T. A hexanucleotide element directs microRNA nuclear import. Science 315: 97-100, 2007. [PubMed: 17204650] [Full Text: https://doi.org/10.1126/science.1136235]
Jiao, J., Herl, L. D., Farese, R. V., Jr., Gao, F.-B. MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia. PLoS One 5: e10551, 2010. Note: Electronic Article. [PubMed: 20479936] [Full Text: https://doi.org/10.1371/journal.pone.0010551]
Luna, C., Li, G., Qiu, J., Epstein, D. L., Gonzalez, P. Role of miR-29b on the regulation of the extracellular matrix in human trabecular meshwork cells under chronic oxidative stress. Molec. Vis. 15: 2488-2497, 2009. [PubMed: 19956414]
Mersey, B. D., Jin, P., Danner, D. J. Human microRNA (miR29b) expression controls the amount of branched chain alpha-ketoacid dehydrogenase complex in a cell. Hum. Molec. Genet. 14: 3371-3377, 2005. [PubMed: 16203741] [Full Text: https://doi.org/10.1093/hmg/ddi368]
Mott, J. L., Kobayashi, S., Bronk, S. F., Gores, G. J. mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 26: 6133-6140, 2007. [PubMed: 17404574] [Full Text: https://doi.org/10.1038/sj.onc.1210436]
Sampath, D., Liu, C., Vasan, K., Sulda, M., Puduvalli, V. K., Wierda, W. G., Keating, M. J. Histone deacetylases mediate the silencing of miR-15, miR-16, and miR-29b in chronic lymphocytic leukemia. Blood 119: 1162-1172, 2012. [PubMed: 22096249] [Full Text: https://doi.org/10.1182/blood-2011-05-351510]
Smith, K. M., Guerau-de-Arellano, M., Costinean, S., Williams, J. L., Bottoni, A., Cox, G. M., Satoskar, A. R., Croce, C. M., Racke, M. K., Lovett-Racke, A. E., Whitacre, C. C. miR29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis. J. Immun. 189: 1567-1576, 2012. [PubMed: 22772450] [Full Text: https://doi.org/10.4049/jimmunol.1103171]
Xu, H., Cheung, I. Y., Guo, H.-F., Cheung, N.-K. V. MicroRNA miR-29 modulates expression of immunoinhibitory molecule B7-H3: potential implications for immune based therapy of human solid tumors. Cancer Res. 69: 6275-6281, 2009. [PubMed: 19584290] [Full Text: https://doi.org/10.1158/0008-5472.CAN-08-4517]
Zhang, Y., Chen, B., Li, D., Zhou, X., Chen, Z. LncRNA NEAT1/miR-29b-3p/BMP1 axis promotes osteogenic differentiation in human bone marrow-derived mesenchymal stem cells. Path. Res. Pract. 215: 525-531, 2019. [PubMed: 30638953] [Full Text: https://doi.org/10.1016/j.prp.2018.12.034]