Transcriptome Dynamics and Potential Roles of Sox6 in the Postnatal Heart

Abstract

The postnatal heart undergoes highly coordinated developmental processes culminating in the complex physiologic properties of the adult heart. The molecular mechanisms of postnatal heart development remain largely unexplored despite their important clinical implications. To gain an integrated view of the dynamic changes in gene expression during postnatal heart development at the organ level, time-series transcriptome analyses of the postnatal hearts of neonatal through adult mice (P1, P7, P14, P30, and P60) were performed using a newly developed bioinformatics pipeline. We identified functional gene clusters by principal component analysis with self-organizing map clustering which revealed organized, discrete gene expression patterns corresponding to biological functions associated with the neonatal, juvenile and adult stages of postnatal heart development. Using weighted gene co-expression network analysis with bootstrap inference for each of these functional gene clusters, highly robust hub genes were identified which likely play key roles in regulating expression of co-expressed, functionally linked genes. Additionally, motivated by the role of the transcription factor Sox6 in the functional maturation of skeletal muscle, the role of Sox6 in the postnatal maturation of cardiac muscle was investigated. Differentially expressed transcriptome analyses between Sox6 knockout (KO) and control hearts uncovered significant upregulation of genes involved in cell proliferation at postnatal day 7 (P7) in the Sox6 KO heart. This result was validated by detecting mitotically active cells in the P7 Sox6 KO heart. The current report provides a framework for the complex molecular processes of postnatal heart development, thus enabling systematic dissection of the developmental regression observed in the stressed and failing adult heart.

Wnt11 regulates cardiac chamber development and disease during perinatal maturation

“…Genes from these modules were preserved between the 2 ventricles and enriched in fatty acid metabolism and PPAR signaling, indicating concordant activation of the fatty acid metabolism pathway at P3. Using quantitative reverse transcription PCR (qRT-PCR) we demonstrated that the expression levels of 14 selected genes involved in fatty acid β oxidation and glycolysis exhibited reciprocal regulation between the P0 and P3 time points, indicating a synchronized molecular switch from glucose metabolism to fatty acid utilization pathway, as has been previously reported (36,37). This suggests that metabolic switch occurs as early as P3 in both ventricles in the neonatal mouse heart (Supplemental Figure 1).…”

Huntington’s disease phenotypes are improved via mTORC1 modulation by small molecule therapy

“…NV-5297 treatment was initiated during the period of heart growth and did not significantly increase heart size. It is possible that initiating treatment earlier or using a higher dose may result in heart sizes closer to WT, though other systemic factors and molecular pathways could also be implicated [ 58 ]. Regardless, previous work has found that small heart size is not associated with functional abnormalities in this model; furthermore, constitutive mTORC1 activation through genetic modalities likewise did not affect adult heart size [ 19 ].…”

Emerging roles of Sox6 in the renal and cardiovascular system

“…They showed cardiac specific Trbp KO mice express lower miR-208a and overexpress Sox6 that result into progressive cardiomyopathy and lethal heart failure (Ding et al, 2015). In another report, Chung-Il An et al 2016, the authors identified Sox6 as key transcription factors suppressing cell proliferation and fine-tuning fetal gene expressions during postnatal heart development to culminate in the complex functional heart (An et al, 2016). Yousefzadeh et al (2017) reported that fetal hypothyroidism decreases cardiac performance as a result of decreased ratio of α-MHC:β-MHC expressions in adult rats.…”

“…In another report, An et al. 2016, the authors identified Sox6 as key transcription factors suppressing cell proliferation and fine‐tuning fetal gene expressions during postnatal heart development to culminate in the complex functional heart (An et al., 2016). Yousefzadeh et al.…”

“…GWAS studies associate Sox6 SNPs with human hypertension across ethnicities (Johnson et al., 2011) and imply great potential of functional studies for Sox6 in hypertensive animal models to discern the Sox6 function and establish molecular pathway in hypertension (Saleem et al., 2020). The investigations in the field of cardiomyopathy and diabetes revealed that Sox6 is primarily regulated by various types of miRNAs (An et al., 2016; Bai et al., 2016). Sox6 is a target gene for the miRNAs which are functionally important in regulating a number of cardiac and skeletal muscles functions.…”