Figure 1: Top: biological system of interest, middle: concept of epigenetic mechanisms, bottom: example of genome-wide approaches with wild-type and mutant epigenetic regulator.
The Noh group studies chromatin links vital for neurodevelopment and disease.
Previous and current research
Chromatin, the faithful association of genomic DNA with histone proteins, exists as the physiological form of our genome and the substrate for processes that regulate cellular gene expression. Numerous diseases are associated with mutations in genes that encode for chromatin-binding and/or chromatin-modifying enzymes, which together act as epigenetic regulators. Combining neurobiology and chromatin biology, we aim to study the molecular mechanisms that link genetic mutations encoded in epigenetic regulators to the widespread chromatin alterations associated with brain diseases. A central question grounding our research is how the chromatin modification network engages in brain development, function and disease.
Previously, our team studied a cellular pathway of ischemia-induced neuronal death, and showed that the transcriptional repressor REST causes epigenetic remodelling and repression of multiple target genes including AMPA receptor in postischemic neurons. We further demonstrated that REST knockdown prevents neuronal death in a clinically relevant in vivo model of ischemia. During the past few years, we uncovered the localisation and function of a histone H3 variant, H3.3. Guided by distinct chaperone systems, H3.3 marks the genomic regions of histone turnover. We mapped the genome-wide localisation of H3.3 in mouse embryonic stem cells (mESCs) and neuronal precursor cells, and further expanded to terminally differentiated neurons for studying its functional role in promoting neuronal plasticity. In addition, we revealed the molecular mechanisms that underlie DNA methylation, specifically the interplay between histone post-translational modifications and DNA methylation, and identified the biological function of this interaction in cell lineage specification.
Future projects and goals
We aim to study chromatin regulation, its interpretation during brain development, and its misinterpretation in relation with brain cognitive and developmental diseases. We will use differentiating neurons from mESCs and human induced pluripotent cells (hiPSCs) to model developmental stages and facilitate the necessary genetic manipulations / engineering. Defining the ‘epigenetic landscape’ – both in normal and abnormal brain cells – will help provide novel targets for therapeutic intervention for cognitive and developmental diseases of the brain.
Our research projects are to:
- Determine combinatorial histone modifications that link de novo DNA methyltransferase location/function during neuronal lineage commitment.
- Identify the location/function of mutated histones and epigenetic regulators specific to cognitive deficits, and explore alterations of the epigenetic landscape in developing neurons.
- Investigate PHD (Plant Homeo Domain)-containing epigenetic regulators that integrate specific signalling pathways into developmental transcription programmes.