Whole Blood Gene Expression Reveals Specific Transcriptome Changes in Neonatal Encephalopathy

Abstract

Background: Variable responses to hypothermic neuroprotection are related to the clinical heterogeneity of encephalopathic babies; hence better disease stratification may facilitate the development of individualized neuroprotective therapies. Objectives: We examined if whole blood gene expression analysis can identify specific transcriptome profiles in neonatal encephalopathy. Material and Methods: We performed next-generation sequencing on whole blood RNA from 12 babies with neonatal encephalopathy and 6 time-matched healthy term babies. Genes significantly differentially expressed between encephalopathic and control babies were identified. This set of genes was then compared to the host RNA response in septic neonates and subjected to pathway analysis. Results: We identified 950 statistically significant genes discriminating perfectly between healthy controls and neonatal encephalopathy. The major pathways in neonatal encephalopathy were axonal guidance signaling (p = 0.0009), granulocyte adhesion and diapedesis (p = 0.003), IL-12 signaling and production in macrophages (p = 0.003), and hypoxia-inducible factor 1α signaling (p = 0.004). There were only 137 genes in common between neonatal encephalopathy and bacterial sepsis sets. Conclusion: Babies with neonatal encephalopathy have striking differences in gene expression profiles compared with healthy control and septic babies. Gene expression profiles may be useful for disease stratification and for developing personalized neuroprotective therapies.

Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy

“…Taken together, our findings stress the leading role of HIF-1α in NE, which is involved in both the melatonin and polo-like kinase cascades 27 – 30 and interacts directly with both RGS1 and SMC4, which are downstream targets of HIF-1α 30 , 31 . These results are also consistent with our previous data, comparing healthy infants and NE, which showed an upregulation of HIF1A and MALAT1 in NE 9 . MALAT1 inhibits HIF-1α ubiquitination and in this way, enhances its activity and increases anaerobic glycolysis.…”

“…The use of gene expression for disease stratification and for elucidation of underlying disease mechanisms has previously been shown in sepsis, paediatric tuberculosis and Kawasaki Disease 6 – 8 . More recently, we have reported that babies with NE have a unique gene expression profile when compared with healthy controls and septic babies, and have an upregulation of the hypoxia inducible transcription factor 1α (HIF1α) 9 . Here, we examined if babies who developed adverse neurodevelopmental outcome after NE, had a unique host blood gene expression profile at birth.…”

Understanding Human Cerebral Malaria through a Blood Transcriptomic Signature: Evidences for Erythrocyte Alteration, Immune/Inflammatory Dysregulation, and Brain Dysfunction

“…Finally, several studies on gene expression analysis using microarrays showed promising results even by using a small number of samples [10,16,49]. Here, despite the limited number of subjects studied for the transcriptome analysis, we obtained sufficient statistical power to identify blood transcriptomic signature which distinguish CM and UM.…”

“…However, deciphering the complex regulatory processes of pathophysiological pathways in human brain remains a challenge due to the inaccessibility of antemortem tissue. Fortunately, the studies on peripheral blood can provide important mechanistic knowledge that may have therapeutic implications [ 13 – 15 ] as shown previously into various infectious and neurological diseases [ 16 – 19 ]. Hence, we speculated that multiple dysregulated pathways may favor CM and that we are able to identify most of them in peripheral blood.…”

Need for more evidence in the prevention and management of perinatal asphyxia and neonatal encephalopathy in low and middle-income countries: A call for action

“…Mechanistic studies and newer methods of classifying neonates with NE based on the underlying injury mechanism would be required to develop specific neuroprotective therapies. Specific gene expression signatures of neonates with NE have been described [ 70 ]. In a small sub-group of 45 neonates recruited to the HELIX trial, a total of 855 genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1 and SMC4 were the most significant [ 71 ].…”