Biology subjects

Geiger, T. M.

Publications and source records attributed to Geiger, T. M..

3 recordsLinked to original sources

bioRxiv2026

Leveraging the BAF chromatin remodeling complex for targeted transcriptional rewiring in cancer

Chromatin accessibility is essential for maintaining the fidelity of gene regulation and is dynamically regulated by epigenetic enzymes that are often dysregulated in cancer. The most commonly mutated regulator is the modular, multi-subunit Brahma-associated factor (BAF) chromatin remodeling complex. Previous attempts to exploit BAF complex mutations as potential tumor vulnerabilities using loss-of-function approaches have shown limited clinical success. Here, we instead propose a gain-of-function (GOF) strategy and establish Transcriptional/Remodeling chemical Inducers of Proximity (TRIPs), a class of neomorphic molecules that recruit active BAF complexes to rewire an oncogenic repressor, B-cell lymphoma 6 (BCL6). TRIPs potently induce transcriptional de-repression and apoptosis in Diffuse Large B-cell Lymphoma (DLBCL), enabled by ternary complex formation between BCL6 and BAF. CRISPR knockout screening identifies the PBAF complex as an essential contributor to cellular TRIP efficacy. Finally, we demonstrate that TRIP induces chromatin enrichment of BAF at BCL6-bound sites, resulting in ATPase-dependent eviction of BCL6, and de-repression of pro-apoptotic BCL6 target genes. We establish BAF recruitment for targeted chromatin remodeling as a viable GOF pharmacological strategy for tackling diseases driven by aberrant gene repression.

cancer biology↗

bioRxiv2025

Heterobifunctional Protein Binders Enable Cell Type-Specific Killing Through In-cell Enrichment

Non-catalytic heterobifunctional molecules promise to expand the range of therapeutic options by establishing complexes between key target proteins and accessory presenter proteins equipped with additional properties. Here, we systematically investigate the rational design of such molecules, explore the biochemical basis of complex formation and determine how they achieve cellular efficacy using the endogenously expressed immunophilin FKBP12 and the transcriptional regulator BRD4 as paradigms. We present classes of bifunctional molecules that enable selective, FKBP12-dependent killing of specific cell types at subnanomolar concentrations and allow to differentiate between closely similar bromodomains. We propose that the strongly potentiated efficacy of these bifunctional compounds is based on cellular enrichment through binding to the highly abundant presenter protein FKBP12, a mechanism we term "CellTrap". Our findings substantiate the concept that highly expressed, non-essential proteins can be repurposed as selective recruiters to expand therapeutic windows of existing small-molecule inhibitors, opening new avenues for designing targeted drugs with improved cell-type specificity.

biochemistry↗

bioRxiv2023

Large-scale in-cell photocrosslinking at single residue resolution reveals the molecular basis for glucocorticoid receptor regulation by immunophilins

The large immunophilins FKBP51 and FKBP52 play key roles in the Hsp90-mediated maturation of steroid hormone receptors, which is crucial for stress-related disorders and correct sexual embryonic development, respectively 1-3. A prominent regulatory target is the glucocorticoid receptor (GR), whose activation is repressed by FKBP51 4,5 and facilitated by FKBP52 6,7. Despite their vital roles, the molecular modes of action of FKBP51 and FKBP52 are poorly understood since the transient key states of FKBP-mediated GR-regulation have remained experimentally elusive. Here we present the architecture and functional annotation of FKBP51-, FKBP52- and p23-containing Hsp90-apoGR preactivation complexes, trapped by systematic incorporation of photoreactive amino acids 8,9 inside human cells. The identified crosslinking sites depended on a functional Hsp90 chaperone cycle, were disrupted by GR activation, and clustered in characteristic patterns, defining the relative orientation and contact surfaces within the FKBP/p23-apoGR complexes. Strikingly, GR binding to the FKBPFK1 but not the FKBPFK2 domains were modulated by FKBP ligands, explaining the lack of FKBP51-mediated GR derepression by certain classes of FKBP ligands. These findings show how FKBP51 and FKBP52 differentially interact with the apoGR ligand binding domain, they explain the differentiated pharmacology of FKBP51 ligands, and provide a structural basis for the development of FKBP ligands with higher efficacy.

biochemistry↗