biomodal Seminar Session at Altos Labs

DNA comprises molecular information stored in genetic and epigenetic bases, both of which are vital to our understanding of biology in health and disease. The interaction of genetics with the epigenome plays a causal role in cell fate, ageing, and disease development.

We introduce duet multiomics solution +modC, a single base-resolution sequencing methodology that sequences complete genetics and cytosine modifications in a single workflow, enabling the identification of genetic variants and quantification of modified cytosine levels in a single experiment, at high accuracy for both genetics and epigenetics. This method is compatible with low quantities of input material, enabling the measurement of genetics and methylation in cfDNA, increasing the information available to identify traces of disease using liquid biopsy. The phased nature of the technology, whereby genetic and epigenetic information is available simultaneously on the same DNA fragment, enables the study of genetic and epigenetic co-variation such as in allele-specific methylation (ASM), whereby differential methylation patterns are observed between heterozygous variants. This technology enables simultaneous multiomic information to be gathered unlike ever before, and will help to understand the dynamism of biology throughout health and disease.

The reprogramming process is capable of reversing multiple hallmarks of ageing, however complete reprogramming to iPSCs does not appear to be required for this, as molecular features such as the epigenome are already rejuvenated by the maturation phase of iPSC reprogramming. We have developed a method called “maturation phase transient reprogramming”, where the factors required for reprogramming (OSKM) are expressed until this rejuvenation point and then withdrawn.

Applying MPTR to dermal fibroblasts from middle age donors, cells temporarily lose and then reacquire their fibroblast identity. Excitingly, this process substantially rejuvenates multiple cellular attributes including transcriptomic and DNA methylation ageing clocks. We are now investigating the effect of MPTR on the genome and epigenome in more detail and have performed 5-letter sequencing on fibroblasts after MPTR. We have found that cells after MPTR possess genetic changes characteristic of AID activity, which could be the result of DNA methylation remodelling. In addition, 5L sequencing has enabled us to examine allele-specific methylation, which we found to be particularly increased on the X chromosome after MPTR. This sequencing technology is enabling us to better understand the safety of MPTR as well as the mechanisms that may be responsible for rejuvenation.