Overview
My group is interested in understanding how miRNAs and their gene targets contribute to maintain pancreatic ß-cell identity and function, which is altered in type 2 diabetes (T2D).
In recent years, we have been studying the role that miRNAs play in AMPK-dependent regulation of ß-cell function. AMPK is a critical energy sensor and a suggested target of widely used antidiabetic drugs such as metformin. Our earliest work (Martinez-Sanchez et al., 2018) demonstrated that AMPK regulates the expression of several miRNAs important for ß-cell proliferation, survival and differentiation. An example is miR-184, essential for ß-cell compensatory proliferation during pregnancy and diabetes.
More recently, we have discovered that miR-125b is up-regulated by hyperglycaemia via AMPK in mouse and human islets and that high levels of this miRNAs are deleterious for ß-cell function (Cheung, Pizza et al., 2022). Using an unbiased, high-throughput approach, we identified several miR-125b gene targets that might mediate some of the effects of miR-125b in ß-cells.
Currently, we are working hard to decipher the molecular mechanism by which miR-125b and its targets control ß-cell function and to develop novel approaches to target miRNA action in these cells. We are doing so with the support of funders such as MRC and DUK and in collaboration with several other groups within and outside Imperial College.
With our work, we hope to gain a better understanding of the importance of these small molecules in the maintenance of glucose homeostasis and aid the development of more efficient drugs for the treatment of diabetes.
Cheung, Pizza et al., Diabetes, 2022. MiR-125b is a negative regulator of beta cell function and targets genes involved in lysosomal and mitochondrial homeostasis.
Martinez-Sanchez et al., FASEBJ, 2018. miRNAs regulated by AMPK are involved in pathways important for b-cell function. A, B) Cytoscape-generated layout of down-regulated (square, red nodes) (A) and up-regulated (square, green nodes) (B) miRNAs and their predicted targets that are up-regulated (circle, green nodes) (A) and down-regulated (circle, red nodes) (B), respectively, in bAMPKdKO vs. control islets. Node size represents the degree of the fold change (the larger, the stronger). The intensity of the gene node color (circles) indicates the target prediction score according to TargetScan (the darker, the stronger)
Rutter et al., Biochem J., 2015. In the ß-cell, glucose metabolism is coupled to insulin secretion. Regulatory molecules, including fatty acids and fatty acid derivatives influence this proccess by several uncompletely-understood mechanisms.
Martinez-Sanchez et al., Mol Endocrinol., 2015. Depletion of mature miRNAs specifically in the ß-cell (KO: Dicer KO) leads to impaired insulin secretion and, eventually, ß-cell death. The figure represents a control (C) and Dicer KO (KO) pancreatic islet.
Publications
Primary peer-reviewed:
- Cheung, R., Pizza, G., et al., and Martinez-Sanchez, A. Glucose-dependent miR-125b is a negative regulator of β-cell function. DIABETES. 2022.
- Nguyen-Tu, MS., Harris J., Martinez-Sanchez, A. et al. Opposing effects on regulated insulin secretion of acute versus chronic stimulation of AMP-activated protein kinase. DIABETOLOGIA 2022.
- Mousavy Gharavy, SN., Owen, B., Millership, SJ., Chabosseau, P., Pizza, G., Martinez-Sanchez, A. et al. Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis. DIABETOLOGIA. 2021.
- Nguyen-Tu, MS., Martinez-Sanchez, A. et al. Adipocyte-specific deletion of Tcf7l2 induces dysregulated lipid metabolism and impairs glucose tolerance in mice. DIABETOLOGIA. 2020
- Martinez-Sanchez, A.* et al. * co-corresponding author. High through-put identification of miR-145 targets in human articular chondrocytes. LIFE (Basel). 2020.
- Georgiadou, E., Haythorne, E., Dickerson, MT., Lopez-Noriega, L., Pullen, TJ., da Silva Xavier, G., Davis, SPX., Martinez-Sanchez, A. et al. The pore-forming subunit MCU of the mitochondrial Ca2 uniporter is required for normal glucose-stimulated insulin secretion in vitro and in vivo in mice. DIABETOLOGIA. 2020.
- Clough, TJ., Baxan, N., Coakley, EJ., Rivas, C., Zhao, L., Leclerc, I., Martinez-Sanchez, A.*, Rutter, GA., Long, NJ. * co-corresponding author. Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of β-cell-dependent contrast enhancement in the pancreas. DALTON TRANS. 2020.
- Martinez-Sanchez, A.* et al. * co-corresponding author. MiR-184 expression is regulated by AMP-activated protein kinase (AMPK) in pancreatic islets. FASEB J. 2018.
- Martinez-Sanchez, A. et al. Disallowance of Acot7 in β-cells is required for normal glucose tolerance and insulin secretion. DIABETES. 2016.
- Yavari, A., Stocker CL., Ghaffari S., Wargent ET., Steeples V., Czibik, G., Bellahcene M., Woods A., Martínez de Morentin PB., Cansell C., Lam BY., Petkevicius, K., Nguyen-Tu MS., Martinez-Sanchez A. et al. Chronic Activation of γ2 AMPK Induces Obesity and Reduces Beta Cell Function. CELL METABOLISM. 2016.
- Seidl, C.I., Martinez-Sanchez, A. and Murphy, C.L. Derepression of microRNA-138 contributes to loss of the human articular chondrocytes phenotype. Arthritis Rheumatol. 2016.
- Martinez-Sanchez, A. et al. DICER inactivation identifies pancreatic β-cell “disallowed” genes targeted by microRNAs. MOL ENDOCRINOL. 2015.
- Kone, M., Pullen, TJ., Sun G., Ibberson, M., Martinez-Sanchez, A. et al. LKB1 and AMPK differentially regulate pancreatic beta cell identity. FASEB J. 2014.
- Martinez-Sanchez, A. and Murphy C.L. MiR-1247 functions by targeting cartilage transcription factor SOX9. J. BIOL CHEM. 2013.Martinez-Sanchez, A. et al. Regulation of human chondrocyte function through direct inhibition of cartilage master-regulator SOX9 by miRNA-145., J BIOL CHEM. 2012.
- Dudek, K.A., Lafont, J.E., Martinez-Sanchez, A. and Murphy CL. Type II collagen expression is regulated by tissue-specific miR-675 in human articular chondrocytes. J. BIOL CHEM. 2010.
- Cuesta, R.*, Martinez-Sanchez, A.*, and Gebauer, F. * co-first author. MiR-181a regulates cap-dependent translation of p27(kip) mRNA in myeloid cells. MOL CELL BIOL. 2009
Pre-prints (BioRxiv)
- Chabosseau, P., Young, F.Y., Delgadillo-Silva, L.F., Lee, E.Y., Li, S., Gandhi, N., Wastin, J., Lopez-Noriega, L., Leclerc, I., Ali, Y., Hughes, J.W., Sladek, R., Martinez-Sanchez, A. and Rugger, G.A. Molecular phenotyping of single pancreatic islet leader beta cells by “Flash-Seq”. 2022. (Under revision in Life Sciences)
- Lopez-Noriega, L., Callingham, R., Martinez-Sanchez, A., et al., The long non-coding RNA Pax6os1/PAX6-AS1 modulates pancreatic β-cell identity and function. BioRxiv (BIORXIV/2020/209015). 2020.
Reviews/book chapters/editorials
- Georgia, S., Arda, H.F., Martinez-Sanchez, A. and Dhawan, S. Editorial: Epigenetics of Glucose Homeostasis. FRONT ENDOCRINOL. 2022.
- Salowka, A and Martinez-Sanchez, A. Molecular mechanisms of nutrient-mediated regulation of microRNAs in pancreatic β-cells. FRONT ENDOCRINOL. 2021.
- Rutter, GA., Georgiadou E., Martinez-Sanchez A. and Pullen TJ. Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity. DIABETOLOGIA. 2020.
- Martinez-Sanchez, A.* et al. * co-corresponding author. Manipulation and measurement of AMPK activity in pancreatic islets. Methods Mol Biol. 2018.
- Martinez-Sanchez, A., Rutter, G.A. and Latreille M. MiRNAs in β-cell development, identity and disease. FRONT GENET. 2017.
- Rutter, GA., Pullen, TJ., Hodson, DJ. and Martinez-Sanchez, A. Pancreatic β-cell identity and the control of insulin secretion. BIOCHEM J. 2015.
- Martinez-Sanchez, A. and Murphy, C.L. MicroRNA target identification – Experimental approaches. Biology (Basel). 2013
Group photos
Enjoying some pizza in the lab
Dr Pizza and Dr Cheung graduate!
Group members
WE ARE RECRUITING: 2 postdoctoral positions available:
https://www.nature.com/naturecareers/job/12795746/research-associate-x2-
Current
Sunehera Sarwat (PhD student)
Yumai Lu (MRes student)
Victoria Zhang (BSc student)
Alumni
Dr Grazia Pizza
Dr Rebecca Cheung
Alina Mihalovic
Becca Sherin
Zhiyi Wu
Ming Ming Yang
Anusha Thapa
Anna Salowka
Angelos Spiliopoulus
Annabel Macklin