Galina Apostolova
Experiences that stimulate neural plasticity trigger specific gene regulatory networks (GRNs), leading to the synthesis of essential proteins for modulating synaptic strength, dendritic spine formation, and even neurogenesis. This intricate interplay between neuronal activity and gene transcription empowers the brain to adapt to its environment and enhance its performance through learning and experiences.
In our work, we employ the chromatin organizer SATB2 as a model case to study the role of 3D genome architecture in tuning the expression of plasticity- and cognition-related GRNs. We apply cutting-edge functional genomics approaches to explore how stimulus-induced, persistent 3D epigenome alterations modify target gene activation upon re-stimulation, thus contributing to a cell-wide metaplasticity.
What makes SATB2 a particularly interesting study case is that it not only integrates immediate early gene induction with 3D epigenome remodeling, but also as a late response BDNF-target gene has the potential to regulate homeostatic adaptive processes in the brain. Investigating the contribution of SATB2-driven 3D genome alterations in these processes is a key research focus of the group.
Focal points of interest on GABA cells
- Experience-dependent inhibitory plasticity
- Re-purposing of developmental mechanisms, e.g. morphogen signalling and/or cell-type specific master regulators, in reorganizing cortical and hippocampal local circuits in response to experience.
- Signalling cascades and candidate genes, downstream of activity-induced transcriptional regulators, and their mode of action (cell-autonomous or non-cell-autonomous, via trans-synaptic signalling) in regulating the neuronal excitation–inhibition balance (formation/plasticity of inhibitory synapses onto pyramidal cells and of excitatory synapses onto inhibitory neurons).
Technical proficiency and instrumentation
- Our lab has solid expertise in a large number of functional genomics assays (in situ HiC, ATAC-seq, CUT&RUN, ChIP-seq, bulk/single nuclear RNA-seq).
- We employ as model systems murine primary cortical neurons, human iPSC-derived NGN2 neurons, and SATB2 conditional knockout mouse lines.
- We apply the INTACT Cre-inducible Sun1-GFP transgene system, coupled with fluorescence-activated nuclear sorting (FANS), to isolate and profile nuclei from different neuronal subtypes of adult mouse brain.
- Our lab is fully equipped for carrying out functional genomics experiments (Agilent 4150 Tape Station, Covaris M220 Ultrasonicator) and AAV-mediated stereotaxic viral gene deliveries.
Aspirations for the next 5 years
Our overarching goal is to shed light on the complex cell-type specific transcriptional mechanisms, which underpin the experience-dependent inhibitory plasticity. By employing the appropriate mouse and human models, we would like to provide novel insights into the specific molecular cascades, e.g. selective expression of cell-surface molecules, chemokine ligands/receptors, and morphogens, triggered by activity-induced master regulators, and understand how they contribute to the reshaping of inhibitory circuits in response to experience.
References
- Wahl N, Espeso-Gil P, Chietera P, Laighneach A, Morris DW, Rajarajan P, Akbarian S, Dechant G, Apostolova G* SATB2 organizes the 3D genome architecture of cognition in cortical neurons. Molecular Cell (2024) DOI: 10.1016/j.molcel.2023.12.024
- Feurle P, Abentung A, Cera I, Wahl N, Ablinger C, Bucher M, Stefan E, Sprenger S, Teis D, Fischer A, Laighneach A, Whitton L, Morris DW, Apostolova G*, Dechant G. SATB2-LEMD2 interaction links plasticity in nuclear shape to gene regulation underpinning cognition. The EMBO Journal (2021) 40(3), e103701. DOI: 10.15252/embj.2019103701
- Jaitner C, Reddy C, Abentung A, Whittle N, Rieder D, Delekate A, Korte M, Jain G, Fischer A, Sananbenesi F, Cera I, Singewald N, Dechant G, Apostolova G*. Satb2 determines miRNA expression and long-term memory in the adult central nervous system. eLife (2016);5:e17361. DOI: 10.7554/eLife.17361
* corresponding author
