Page 127 - CSIR-IGIB Annual Report 2020-21
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Transgenerational effect of Vitamin B12 deficiency One carbon metabolism (OCM) involves sets of
Vitamin B12, is an essential micronutrient, biochemical reactions, which serve to activate and
deficiency of which, is associated with various transfer one carbon unit for different biosynthetic
complex disorders. Vitamin B12 deficiency is processes including methylation and nucleotide
prevalent in India, mainly due to low intake and biosynthesis. Imbalance of OCM is associated with
malabsorption. Perturbation in parental different diseases such as cardiovascular diseases,
nutritional status of micronutrients like vitamin neurological disorder, cystic fibrosis, osteoporosis
B12 prior to mating or during gestational period etc. Three intermediates of OCM- cysteine,
can alter the epigenetic signatures in the germ homocysteine and SAH (S-adenosyl
cells and embryo leading to manifestation of homocysteine) have been reported to be toxic to
complex metabolic disorders in the offspring. eukaryotes. Using Saccharomyces cerevisiae as a
Relation of maternal nutritional deficiency and risk model organism, we explore the mechanism of the
of complex disorder in progeny has been well toxic effect of these metabolites. Cysteine,
established. However, the effect of paternal homocysteine and SAH cause growth defect in
micronutrient status has often been ignored wild type yeast. Cysteine and homocysteine
although it has the potential to influence long toxicity are rescued by pyruvate, leucine and keto-
term health of the offspring. We evaluated the isocaproate, whereas SAH toxicity can only be
effects of vitamin B12 deficiency in the health of rescued by its precursor, SAM. Using proteomics,
the offspring and found that maternal vitamin B12 we found that these metabolites alter proteins
deficiency leads to atherogenic risk in male but not involved in amino acid metabolism, energy
female pups. The male pups have high plasma metabolism, ribosome biogenesis and cytoplasmic
triglyceride levels and low HDL levels - translation. Through a comprehensive genome
characteristic hallmarks of cardiometabolic wide mutant screen, we identified three genes
diseases. Epigenetic, proteomic and metabolomic (NCL1, CTR1, and YML082W) that are required for
profiling of liver from F1 offspring born to vitamin leucine mediated rescue in presence of elevated
B12 deficient mothers, at 3 months revealed cysteine. Amongst these, NCL1, is a SAM
alteration in amino acid levels, carbohydrate and dependent m5C- methyltransferase, and
lipid metabolism, which appears to be through methylates cytosine to m5C at several positions in
alternation of PPARα. The gender specific various tRNA. However, a leucine tRNA, tRNALeu
outcomes of maternal vitamin B12 deficiency can (CAA), is the only tRNA where it methylates at the
be partially explained by dysregulated corticoids wobble position. In ∆ncl1, cysteine decreases the
and steroid hormone biosynthesis pathway. level of TCA intermediates, increases
Rehabilitation of vitamin B12 reversed most of mitochondrial copy number, causing inability to
these changes. In F2 generation, the offspring grow in a complete non-fermentable media and
showed adaptation and had little effect of leads to accumulation of ROS. This signifies that
maternal vitamin B12 deficiency. To understand mitochondrial respiration is necessary for survival
the role of micronutrient deficiency in paternal during cysteine stress. Keto-isocaproate but not
lineage, a transgenerational vitamin B12 deficient leucine partially restored the effect of cysteine in
rodent model has now been generated in ∆ncl1. Cysteine can auto-oxidize in the presence
collaboration with CSIR-Centre For Cellular And of copper to form cystine, a comparatively less
Molecular Biology. In the future, we will undertake toxic metabolite. Thus, this may be a possible
a multi-omics approach to understand the reason for hypersensitivity of Δctr1 strain, which is
changes in offspring born to vitamin B12 deficient a knockout strain for a copper transporter, CTR1.
fathers and evaluate if vitamin B12 deficiency
induced alteration of lipid levels are directly Lipid alteration in Vitamin B12 deficiency
mediated by PPARα. Vitamin B12 has various roles in maintaining cell
homeostasis. Its deficiency is often associated
Toxicity of one carbon metabolism with cardiovascular disease, a metabolic disorder,
Annual Report 2020-21 124
