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l3mbtl1

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Official Full Name
l(3)mbt-like 1 (Drosophila)
Background
This gene represents a polycomb group gene. The encoded protein functions to regulate gene activity, likely via chromatin modification. The encoded protein may also be necessary for mitosis. Alternatively spliced transcript variants encoding different isoforms have been identified.
Synonyms
L3MBTL1; l(3)mbt-like 1 (Drosophila); l(3)mbt (Drosophila) like , l(3)mbt like (Drosophila) , L3MBTL; lethal(3)malignant brain tumor-like protein 1; dJ138B7.3; DKFZp586P1522; KIAA0681; lethal (3) malignant brain tumor l(3); RGD1307316; H-L(3)MBT; H-l(3)mbt protein; L(3)mbt protein homolog; L(3)mbt-like; L3MBT; LMBL1_HUMAN; L3MBTL

Recent Progress

Lethal 3 malignant brain tumor-like protein(L3MBTL) is discovered in Drosophila, and is considered as a suppressor of malignant transformation of neuro-blasts and ganglion mother cells in the optic centers of the brain. Overexpression of L3MBTL in a glioma cell line can lead to improper nuclear segregation and cytokinesis, which produce multinucleated cells(Fig. 1).

Fig. 1. Alternate Models for L3MBTL1 Compaction of Nucleosomal Arrays. (Trojer et al, 2007)

Researchers have discovered that L3MBTL1 has the potential of repressing the ability of stem cells to drive hematopoietic-specific transcriptional programs. This is achieved by L3MBTL1 moderating the expression of SMAD5 and decreasing its recruitment to targeted regulatory regions. Researchers also discovered that in mature hematopoietic cell populations, L3MBTL1 has a role in regulating SMAD5 target gene expression, hence influences the erythroid differentiation. These findings could be helpful in the development of therapeutic approaches for patients with anemia.

Through exposing the L3mbtl1 null mutant mice to a wide range of tests in the context of social isolation, which serves as a stressor to invoke depression-related behavior in susceptible mice. In several behavioral paradigms, researcher connect L3mbtl1 loss-of-function with significant decreases in depression and anxiety. However, L3mbtl1 may has nothing to do with more generalized neurological dysfunction. This is because cognition and memory remained unchanged in comparison to controls.

Investigators revealed that L3mbtl1 could be downregulated by neuronal activity. This feature of L3mbtl1 is important for synaptic response and downscaling. Through genome-scale mapping of L3mbtl1 occupancies, researchers discovered Ctnnb1 as a key gene downstream of L3mbtl1. Importantly, this occupancy is regulated by neuronal activity. The knockout neurons of L3mbtl1 displayed decreased Ctnnb1 expression. Researchers discovered that through transfecting Ctnnb1 in L3mbtl1 knockout neurons, synaptic transmission was enhanced and homeostatic downscaling restored.

To investigate the interaction between L3mbtl1 and the KME reader protein, a series of compounds was synthesized by replacing UNC669’s aromatic component with pyrimido[4,5-d]pyrimidin-4( 3H)-ones. Through screening these compounds with Alpha Screen, a compound 8a was produced. Three selective and potent L3MBTL1 binders were generated from exploration of 5-position of compound 8a. They showed no significant activity against the other KME reader proteins in the panel.

In order to quantify and compare peripheral plasma (PP) and follicular fluid (FF) retinoid levels, in particular the ATRA in women who are undergoing in vitro fertilization (IVF), also to investigate the relationship between retinoid levels and embryo quality, researchers evaluated retinoid levels in PP and FF from 79 women undergoing IVF at the time of oocyte retrieval and corresponding embryo quality. This was achieved on a daily basis after retrieval for 3 days until uterine transfer. In FF versus PP, results revealed distinctive levels of retinoid metabolites and isomers. It was discovered that a considerably larger percentage of high-quality grade I embryos derived from the largest than the smallest follicles. Investigators also demonstrated that the expression of imprinted gene L3MBTL1 exist abnormally in the early and late stages of pregnancy after ART. This may cause the mother and offspring born with abnormality. Also, in ART offspring with imprinted gene L3MBTL1 methylation, status of the promoter region was changed as well. It was also revealed that aberrant methylation of the promoter is one of the ways of the regulation of gene expression.

References:

  1. Perna, F., et al. "The Polycomb Group Protein L3MBTL1 Represses a SMAD5-Mediated Hematopoietic Transcriptional Program in Human Pluripotent Stem Cells." Stem Cell Reports 4.4(2015):658-669.
  2. Shen, E. Y., et al. "Cognition and mood-related behaviors in L3mbtl1 null mutant mice. " Plos One 10.4(2015):e0121252.
  3. Mao, W., et al. "Activity-Induced Regulation of Synaptic Strength through the Chromatin Reader L3mbtl1." Cell Reports 23.11(2018):3209.
  4. Hao, Zhou, et al. "Design and Synthesis of Pyrimido[4,5-d]pyrimidin-4(3H)-ones as Selective L3MBTL1 Binders." Chemical Journal of Chinese Universities 37.7(2016):1293-1301.
  5. Sun, L., et al. "Expression and methylation status of imprinted genes PEG10,L3MBTL1 in the children derived from assisted reproductive technology." Fertility & Sterility 100.3(2013):S481-S481.