Wei Guo

Education

PhD China Agricultural University

Research Summary

Posttranscriptional process and RNA metabolism in muscle structure and function

Research Detail

For genes to produce their final functional products (proteins or non-coding RNAs), the RNA transcripts need to be extensively processed after transcription, including splicing, modification, transportation, translation and eventual degradation.  RNA binding proteins (RBPs) are important regulators in each step of the complex processes of RNA metabolism and are increasingly recognized as critical regulators in myogenesis, muscle hypertrophy and disease. Hence, the research program in Guo lab is focused on understanding the role of RBPs in RNA metabolism in myogenesis, muscle growth and disease. The long-term goal in Guo lab is to develop RNA-based approaches to improve human health and animal production efficiency.

1. Splicing regulation of RNA binding protein 20 (RBM20) in heart muscle disease. RBM20 is an RNA binding protein and a muscle specific splicing factor that is highly expressed in heart muscle. We have first reported that RBM20 is a primary regulator of gene TTN, encoding a giant sarcomeric protein titin that is responsible for myocardial stiffness (Guo et al., 2012; Greaser et al., 2008; Li et al., 2013). In addition to TTN, we have also found that RBM20 regulates over 30 genes including calcium handling genes such as Ryr2, triadin and Camk2d. Loss-of-function of RBM20 results in aberrant splicing of these genes and cardiac dysfunction (Guo et al., 2012, 2013, 2018). We propose that correcting abnormal splicing through RBM20 could be a strategy to treat or improve cardiac dysfunction. For example, titin produces two classes of isoforms resulting from alternative splicing regulated by RBM20. One class of isoforms is a shorter and stiffer N2B isoform, and the other is longer and more compliant N2BA isoforms. The ratio of N2B to N2BA isoform is a key determinant for heart ventricular wall stiffness. In healthy heart, the ratio is about 70 to 30, whereas the ratio is increased in diastolic dysfunction. Therefore, manipulating titin isoform ratios through RBM20 could be a therapeutic strategy to reduce stiffness and improve heart function in patients with diastolic stiffness. Our research revealed that RBM20 expression is regulated by the PI3K/Akt/mTOR signaling pathway, suggesting targeting this signaling pathway could be a strategy to regulate titin isoform ratios (Zhu et al., 2015, 2017), and thus improve diastolic dysfunction.
2. Genetic mutations of RBM20 in the pathogenesis of heart failure. In addition to cardiac dysfunction caused by RBM20 loss-of-function, genetic mutations in the arginine/serine rich (RS) domain of RBM20 have been linked to severe dilated cardiomyopathy (DCM) and early onset heart failure. RS domain in RBPs plays a critical role in protein-protein interaction and protein transport. Mutations in RS domain block RBM20 nuclear import and promote ribonucleoprotein (RNP) granules formation (Sun et al., 2020). Interestingly, mutations in other domains do not facilitate RBM20 nucleocytoplasmic transport and promote DCM, suggesting disruption of RS domain is causative for DCM. We have identified that nuclear localization signal (NLS) is located in RS domain and only mutations in NLS results in DCM. Our next goal is to illustrate how NLS mediates RBM20 location and how RBM20 promote RNP granules assembly. Ultimately, we will develop a therapeutic strategy to treat RBM20 granules disease through targeting RBM20 transport and granules disassembly.
3. RBM20 in skeletal muscle myogenesis and growth. Muscle growth is the net effect when protein synthesis exceeds protein degradation. Small changes in either the protein synthesis rate or the rate of protein turnover (degradation rate) have profound effects on net protein deposition and rate of growth. In order to increase the efficiency of lean muscle accretion, a better understanding of those basic biological mechanisms in skeletal muscle tissue is necessary. In addition, myogenesis/muscle regeneration normally occurs after impairment in skeletal muscle function including injury, disease and aging postnatally. Intensive research has been done to address the regenerative mechanisms which are involved in acute muscle injuries and chronic muscle diseases. However, the exact molecular mechanisms and effects on muscle growth and regeneration need be further defined. In addition to heart muscle, RBM20 is also expressed in skeletal muscle with different expression level across muscle types (Chen et al., 2018; Maimaiti et al., 2021). RBM20 also regulates titin splicing in skeletal muscle (Maimaiti et al., 2021; Li et al., 2012). We recently found that RBM20 loss-of-function leads to delayed myogenesis and impaired growth performance across muscles in rats. Titin is also a mechanosensing signal molecule that transduces hypertrophic signaling (Guo and Sun, 2018), so we propose to determine whether RBM20 mediate skeletal muscle hypertrophy through titin mediated hypertrophic signaling.
4. Posttranscriptional regulation in fetal programming. Developmental programming, also known as fetal programming, occurs during formation and development of a life in the womb, a critical period when the cells forming tissues and organs are highly active and undergo rapid differentiation and proliferation. During this specific window of development when the fetus is especially vulnerable, exposure of the fetus to a hostile uterine environment such as poor nutrition or hormonal perturbations may lead to retarded offspring growth and short- and long- term health implications. Nutrition is one of the major intrauterine environmental factors that can reprogram fetal growth and development during gestation in many species such as cattle, swine and sheep. Both maternal under- and over-nutrition can lead to intrauterine growth restriction, reduced birth weight, increased fetal and neonatal mortality, and altered postnatal growth rate, decreased carcass quality and feed efficiency and negative health effects in animals and humans. Currently 18-35% of pregnant women in the US are obese. Human studies have shown that maternal obesity (MO) increases the risk of next generation later-life cardiac dysfunction, suggesting MO is a significant risk factor of origins of adult offspring cardiovascular disease (CVD). However, the cellular and molecular mechanism(s) underscoring the onset and development of adult offspring CVD in the face of MO remain poorly defined. RNA binding motif protein 39 (RBM39), a splicing factor, is highly upregulated in fetal hearts of MO. RBM39 serves as a co-activator of steroid hormone receptor-mediated transcription and interacts with cortisol receptors. In addition, RBM39 plays a vital role in mitochondrial energy metabolism and stress-induced nuclear responses through autophagy. Therefore, we are aiming to understand whether elevated fetal cortisol level by MO from dG75 to newborn leads to altered autophagy and/or mitophagy level in fetal hearts though RBM39-mediated pathway.

Publications

https://www.ncbi.nlm.nih.gov/myncbi/browse/collection/47092037/?sort=date&direction=ascending