First evidence of the influence of a crucial protein over RNA

CiMUS researchers report on ‘Nature Genetics’ the influence of the protein TET2 in the regulation of RNA, the molecule in charge of transmitting genetic instructions to the cellular machinery.

The genetic information responsible for the preservation of the identity of the human species lies within each of the millions of cells that shape our body. This map of life is guarded by deoxyribonucleic acid (DNA) is carefully kept into a highly organized structure, known as chromatin. This “instructions handbook” is of such relevance that any mutation in the DNA sequence or in one of the factors responsible for its organization, cannot only lead to the onset of numerous diseases, but also contributes to the unavoidable ageing process.

Sheltered in the cell nucleus, an exact replica of the DNA is present in all cells of the same individual; however, it is not expressed in the same way in all of them: the reversible modifications that occur on the chromatin allow, for example, that lung and kidney cells from the same person can function differently, even if their genetic material is identical. This chromatin landscape that encompasses several chemical modifications and determines the “cell identity”, is known as epigenetics.

The study of epigenetic regulation is a field of great interest, since this mechanism allows the activation and inhibition of gene expression on demand. However, it is an extremely complex process, which requires the interplay of many specific components (enzymes and cofactors) to establish the appropriate settings that will define a specific cell type.

In the case of gene activation, modifications on DNA structure are mainly produced by a specific family of proteins: the TETs (Ten-Eleven Translocation family); among them, TET2 stands out for its pivotal role in the control of stem cells (known for their great therapeutic potential). Likewise, in recent years it has also been shown that TET2 function is altered in many cancers, including leukemia.

Diana Guallar, first author of the work, together with the rest of the research team from CiMUS. From left to right: Miguel González-Blanco, José Ángel Pardavila and Miguel Fidalgo (Photo: Andrés Ruiz / CiMUS).

An unexpected finding

Despite the enormous efforts devoted by the scientific community to the study of TET2 protein, many of the critical aspects regarding how this “epigenetic factor” performs its function to determine the correct function of cells, or how its deregulation can lead to the appearance of diverse pathologies like cancer or immune disfunctions, remain unclear.

Now, a work from CiMUS published in the prestigious international journal ‘Nature Genetics provides new information about TET2 activity, showing for the first time not only its ability to act on chromatin to regulate DNA, but also an unexpected function on RNA molecules (which are DNA messengers), specifically those related to the control of genes and transposable elements (fragments of DNA capable of moving to different parts of the genome expression).

“We discovered that TET2 is capable of adding the ‘5hmC’ chemical modification to RNA molecules, which appears to be required to control their stability and abundance”, explains Diana Guallar, first author of the investigation that shows that many of the RNA molecules that arise from transposable elements present in our genome can be regulated by TET2 and its fine deposition of 5hmC epigenetic modification.

“It is especially relevant, because these fragments that we call transposable elements represent about half of our genome”, says Guallar. “Research has already related these elements to the onset of many human diseases, including the ageing process itself”, she adds.  “Many recent studies have shown that excessive presence of these elements in our body can be damaging, and lead to the appearance of autoimmune diseases, neurodegenerative disorders or even cancer”.

This work results form an intense collaboration of CiMUS with international laboratories from the United States, Mexico and China, and it has involved two groups from the University of Santiago de Compostela (USC): those led by doctors Miguel Fidalgo  (Stem Cells and Human Diseases) and Miguel González-Blanco (DNA Repair and Genome Integrity), to which Diana Guallar belongs.

The results of this study not only make an important contribution to the scientific knowledge of TET2 function in the epigenetic regulation of stem cells, but also opens new avenues in cancer research, where TET2 functions on RNA have never been evaluated before.


RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells
Diana Guallar, Xianju Bi, Jose Angel Pardavila, Xin Huang, Carmen Saenz, Xianle Shi, Hongwei Zhou, Francesco Faiola, Junjun Ding, Phensinee Haruehanroengra, Fan Yang, Dan Li, Carlos Sanchez-Priego, Arven Saunders, Feng Pan, Victor Julian Valdes, Kevin Kelley, Miguel G. Blanco, Lingyi Chen, Huayan Wang, Jia Sheng, Mingjiang Xu, Miguel Fidalgo, Xiaohua Shen and Jianlong Wang.


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