Redundancy or Necessity? Functional Specificity of Paralogs in SWI/SNF Chromatin Remodelling Complexes During Neurodevelopment

Diplôme Thèse Redundancy or Necessity? Functional Specificity of Paralogs in SWI/SNF Chromatin Remodelling Complexes During Neurodevelopment eng 2026-03-03 2026-03-03 author So Younju 974569 director Braun Simon 930774 Département de médecine génétique et développement (GEDEV) 10.13097/archive-ouverte/unige:192538 urn:nbn:ch:unige-1925385 Sc. Vie - Bioméd. 385 Neurodevelopmental disorders, including autism spectrum disorder, attention deficit hyperactivity disorder and intellectual disability, constitute a spectrum of conditions that impair brain development and function (Gilissen et al., 2014; Parenti et al., 2020). Many of these brain disorders are often associated with genetic mutations in genes encoding chromatin regulators (Valencia and Pașca, 2021). Among them, the SWI/SNF chromatin remodelling complex stands out as one of the most mutated in neurodevelopmental disorders. This complex consists of multiple subunits, many of which exist in several paralogous forms, leading to a high degree of compositional diversity and functional specificity depending on the cellular context. During neurodevelopment, paralog variants of specific subunit families have been shown to confer tissue specificity and to fulfil distinct functional roles throughout neural lineage progression. In this thesis, I investigate the contributions of the SMARCD paralogs, core components of the SWI/SNF complex, to define the cell type specific functions of SMARCD1, SMARCD2 and SMARCD3 during neurodevelopment. Using complementary in vivo and in vitro approaches in mouse neural progenitor cells and neurons, we found that single loss of SMARCD1 or SMARCD3 in the embryonic forebrain produces little effect on neural progenitor maintenance or neuronal differentiation. In contrast, combined loss of both paralogs during early brain development leads to a modest reduction in cortical thickness, indicating a compensatory interplay between SMARCD paralogs. Molecular analyses confirmed this compensatory relationship and further revealed distinct paralog specific functions that likely explain why, in humans, loss of individual SMARCD paralogs can still result in neurodevelopmental disorders. Our data support a model in which SMARCD1 contributes to neural progenitor lineage specification through interaction with DIP3B, whereas SMARCD3 plays a more prominent role in regulating mitochondrial metabolism in neurons, potentially via interaction with the transcription factor NACC1. Together, these findings provide mechanistic insight into paralog specific functions within the SWI/SNF complex and advance our understanding of how chromatin remodelling governs cell type specific regulatory programmes during neural differentiation. Dewey 576.5 135 Département de médecine génétique et développement 21D false 1357 Régulation de la chromatine dans le développement du cerveau 1031 96f1b4d3-542e-4cac-9206-8bc363a7f27c Thesis Public YounJu_thesis_09.03.2026_FINAL.pdf 4858739 application/pdf ce72242af96a25a6b5223e8c653170e3878400fb7712918a68e1030b3c7580a6 609e743d-4b74-4b91-804b-cfa8ce934ab0 Imprimatur Public Attestation_PhD_Defence.pdf 3584154 application/pdf a82fc2d0ebc0ed52d6466bbf354e7ac663ce69ff32f050b33052489d67758456 openAccess Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement

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Redundancy or Necessity? Functional Specificity of Paralogs in SWI/SNF Chromatin Remodelling Complexes During Neurodevelopment				2026	67	64

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