The biological function of the genetic "dark matter" of lupus erythematosus is revealed

  New discoveries in medicine

  ◎Reporter Wang Chun

  On January 8, the international authoritative journal Nature Communications published online the latest research results of the team of Professor Nan Shen from the Institute of Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine: "Systemic Lupus Erythematosus Non-coding Inheritance The site controls the apparent modification of immune cell-specific enhancers to regulate the expression of key microRNAs in diseases.

The research integrates epigenetics, 3D genomics and CRISPR technology to clarify the molecular inheritance of abnormal expression of non-coding RNA, which plays an important regulatory role in the pathogenesis of systemic lupus erythematosus (SLE), in specific immune cell subgroups The scientific mechanism provides a new research paradigm for systematically identifying the biological functions of a large number of SLE non-coding genetic factors and developing cell-specific intervention methods in the future.

  According to Shen Nan, SLE is a chronic autoimmune disease that occurs mostly in women and can cause damage to multiple organs. In severe cases, it can be life-threatening.

However, the cause of the disease is unknown, and there is currently no effective cure.

A large number of studies have shown that genetic and environmental factors are closely related to the occurrence of the disease. For example, in SLE patients, the incidence of identical twins is much greater than that of fraternal twins.

Therefore, research on the functions of the genome that determine inheritance will help reveal the pathogenesis of SLE and develop new prevention and treatment methods.

  Shen Nan's research team has been focusing on related research on genetics and SLE.

In recent years, using traditional first-generation sequencing, advanced second-generation sequencing, and exome sequencing and other methods, a number of disease susceptibility genes and loci related to SLE have been discovered. Related studies have confirmed the genetic susceptibility of SLE and obtained It has been confirmed and widely concerned by international counterparts.

However, current research shows that many disease susceptibility sites exist as genetic signatures rather than functional disease sites. Only by identifying functional genetic susceptibility sites and analyzing the molecular mechanisms can they be used for early detection and diagnosis of diseases. And treatment provide new ideas.

Related research has always been a hot and difficult point in the field of genetics.

  In the human genome, non-coding sequences account for 99%, but these non-coding sequences are not without function.

For example, enhancers, as part of the non-coding sequence, determine in which cells a gene can be expressed and the fate of cell differentiation.

Interestingly, most of the genetically discovered lupus genetic susceptibility sites are located in the non-coding region and in the enhancer region.

Based on the above findings, the researchers guessed that the disease susceptibility sites located in the enhancer region may serve as a label, suggesting which disease susceptibility sites in the genome are functional and which regulatory regions can participate in the occurrence and development of SLE.

  To this end, researchers first comprehensively use multiple omics technologies such as genetics, epiomics, and high-throughput sequencing technologies to determine disease susceptibility sites with potential regulatory functions.

More importantly, the researchers found that the further introduction of the CRISPR activation system into the peripheral blood cells of lupus patients can target the enhancer at the genetic susceptibility site, thereby effectively blocking the abnormal activation of the interferon pathway in lupus patients.

  The study demonstrated a strategy for screening functional disease susceptibility sites and functional regulatory elements, and linked the genetic variation of autoimmune disease risk with the etiology of autoimmune diseases, providing a new approach for the treatment of autoimmune diseases The direction and target point.