Circadian Genes Expression Patterns in Disorders Due to Enzyme Deficiencies in the Heme Biosynthetic Pathway

Abstract

Heme is a member of the porphyrins family of cyclic tetrapyrroles and influences various cell processes and signalling pathways. Enzyme deficiencies in the heme biosynthetic pathway provoke rare human inherited metabolic diseases called porphyrias. Protein levels and activity of enzymes involved in the heme biosynthetic pathway and especially 5′-Aminolevulinate Synthase 1 are featured by 24-h rhythmic oscillations driven by the biological clock. Heme biosynthesis and circadian pathways intermingle with mutual modulatory roles. Notably, heme is a ligand of important cogs of the molecular clockwork, which upon heme binding recruit co-repressors and inhibit the transcription of numerous genes enriching metabolic pathways and encoding functional proteins bringing on crucial cell processes. Herein, we assessed mRNA levels of circadian genes in patients suffering from porphyrias and found several modifications of core clock genes and clock-controlled genes expression, associated with metabolic and electrolytic changes. Overall, our results show an altered expression of circadian genes accompanying heme biosynthesis disorders and confirm the need to deepen the knowledge of the mechanisms through which the alteration of the circadian clock circuitry could take part in determining signs and symptoms of porphyria patients and then again could represent a target for innovative therapeutic strategies.

Analysis of potential biomarkers for diabetic kidney disease based on single-cell RNA-sequencing integrated with a single-cell sequencing assay for transposase-accessible chromatin

“…Nuclear respiratory factor 1 ( Nrf1 ) and pre-B-cell leukemia transcription factor 1 ( Pbx1 ) showed lower chromatin accessibility of their promoter regions in the PTS1 cluster of db/db mice than in those of db/m mice ( P <0.01). Pbx1 is necessary for renal development and is involved in the activation of the nephrin promoter in the proximal tubules [ 17 ], while Nrf1 acts as a cytoprotective factor in cells and plays a regulatory role in diabetes by modulating the level of glutathione [ 18 ] ( Figure 6C , 6D ).…”

Intrahepatic Cholangiocarcinoma and Acute Intermittent Porphyria: A Case Report

“…Likewise, heme upkeeps diatomic gases sensing and signaling, gene transcription/translation, mi-croRNA processing, protein stability, mitochondrial protein import, metabolic pathways, drug detoxification and biological clock functioning. Heme synthesis deficiency can cause porphyrias together with different pathological conditions, including anemias, kidney disease, cerebral hypoperfusion; besides, accumulation of porphyrins triggers toxic effects on hepatocytes, leading to free radical formation, hepatocyte harm and subsequent DNA damage [11][12][13][14][15].…”

Intrahepatic Cholangiocarcinoma and Acute Intermittent Porphyria: A Case Report

“…Likewise, heme upkeeps diatomic gas sensing and signaling, gene transcription/translation, microRNA processing, protein stability, mitochondrial protein import, metabolic pathways, drug detoxification, and biological clock functioning. Heme synthesis deficiency can cause porphyrias together with different pathological conditions, including anemias, kidney disease, and cerebral hypoperfusion; besides, the accumulation of porphyrins triggers toxic effects on hepatocytes, leading to free radical formation, hepatocyte harm, and subsequent DNA damage [11][12][13][14][15].…”