The Roadmap toward Personalized Medicine: Challenges and Opportunities.

In 2019, the International Consortium for Personalised Medicine (ICPerMed) developed a vision on how the use of personalized medicine (PM) approaches will promote "next-generation" medicine in 2030 more firmly centered on the individual's personal characteristics, leading to improved health outcomes within sustainable healthcare systems through research, development, innovation, and implementation for the benefit of patients, citizens, and society. Nevertheless, there are significant hurdles that healthcare professionals, researchers, policy makers, and patients must overcome to implement PM. The ICPerMed aims to provide recommendations to increase stakeholders' awareness on actionable measures to be implemented for the realization of PM. Starting with best practice examples of PM together with consultation of experts and stakeholders, a careful analysis that underlined hurdles, opportunities, recommendations, and information, aiming at developing knowledge on the requirements for PM implementation in healthcare practices, has been provided. A pragmatic roadmap has been defined for PM integration into healthcare systems, suggesting actions to overcome existing barriers and harness the potential of PM for improved health outcomes. In fact, to facilitate the adoption of PM by diverse stakeholders, it is mandatory to have a comprehensive set of resources tailored to stakeholder needs in critical areas of PM. These include engagement strategies, collaboration frameworks, infrastructure development, education and training programs, ethical considerations, resource allocation guidelines, regulatory compliance, and data management and privacy.

Mammalian methyl-binding proteins: what might they do?

CpG islands (CGIs) are regions enriched in the dinucleotide CpG; they constitute the promoter of about 60% of mammalian genes. In cancer cells, some promoter-associated CGIs become heavily methylated on cytosines, and the corresponding genes undergo stable transcriptional silencing. Hypermethylated CGIs attract methyl-CpG-binding proteins (MBPs), which have been shown to recruit chromatin modifiers and cause transcriptional repression. These observations have led to the prevalent model that methyl-CpG-binding proteins are promoter-proximal transcriptional repressors. Recent discoveries challenge this idea and raise a number of questions. Here we discuss the following issues: what are other possible roles for the known MBPs? Why are these proteins not essential in mammals? Are there other MBPs left to discover? Could CpG methylation be nonessential?

The human proteins MBD5 and MBD6 associate with heterochromatin but they do not bind methylated DNA.

BACKGROUND: MBD5 and MBD6 are two uncharacterized mammalian proteins that contain a putative Methyl-Binding Domain (MBD). In the proteins MBD1, MBD2, MBD4, and MeCP2, this domain allows the specific recognition of DNA containing methylated cytosine; as a consequence, the proteins serve as interpreters of DNA methylation, an essential epigenetic mark. It is unknown whether MBD5 or MBD6 also bind methylated DNA; this question has interest for basic research, but also practical consequences for human health, as MBD5 deletions are the likely cause of certain cases of mental retardation. PRINCIPAL FINDINGS: Here we report the first functional characterization of MBD5 and MBD6. We have observed that the proteins colocalize with heterochromatin in cultured cells, and that this localization requires the integrity of their MBD. However, heterochromatic localization is maintained in cells with severely decreased levels of DNA methylation. In vitro, neither MBD5 nor MBD6 binds any of the methylated sequences DNA that were tested. CONCLUSIONS: Our data suggest that MBD5 and MBD6 are unlikely to be methyl-binding proteins, yet they may contribute to the formation or function of heterochromatin. One isoform of MBD5 is highly expressed in oocytes, which suggests a possible role in epigenetic reprogramming after fertilization.