Biology subjects

Sharlandjieva, V.

Publications and source records attributed to Sharlandjieva, V..

3 recordsLinked to original sources

bioRxiv2026

A Unique Promoter Architecture Defines Menin-KMT2A Complex Selectivity

Selective occupancy of chromatin-regulatory complexes is central to developmental gene regulation, yet the sequence determinants of this selectivity remain poorly understood. Using interpretable machine learning, we identify a composite promoter architecture comprising CpG islands flanked by several-kilobase A/T-rich domains (AT-flanks) that denotes high occupancy of the Menin-KMT2A histone-modifying complex at developmental and leukemia-associated genes. Genetic deletion and chromatin-contact analyses show that AT-flanks support KMT2A retention at linked CpG islands. We identify LEDGF as an A/T-rich DNA-associated protein required for Menin engagement at AT-flanks and sustained KMT2A promoter occupancy. AT-flank extent is associated with differential KMT2A loss following pharmacologic disruption of the Menin-KMT2A interaction, providing a genomic basis for heterogeneous target sensitivity to recently approved Menin inhibitors in acute leukemia. Beyond Menin-KMT2A, the same architecture distinguishes promoters with high canonical PRC1 occupancy across diverse cell types, revealing a shared sequence organization associated with distinct chromatin-regulatory states.

molecular biology↗

bioRxiv2026

Menin maintains enhancer-promoter interactions in a leukemia-specific manner

Inhibition of the protein-protein interaction between Mixed Lineage Leukemia (MLL) and Menin is a promising therapy for both high-risk MLL-rearranged and NPM1-mutant (NPM1c) acute leukemias, yet the mechanistic basis of this dependency in distinct contexts remains unclear. By comparing the transcriptional responses of MLL::AF4 and NPM1c leukemia models to Menin inhibition, we find broad, acute transcriptional dysregulation in MLL::AF4 cells, but minor transcriptional consequences in NPM1c cells, despite similarities in Menin promoter occupancy. Using high-resolution Micro Capture-C, we discover that Menin drives enhancer activity and maintains enhancer-promoter contacts in MLL::AF4 cells but not in NPM1c cells. Crucially, Menin is also essential for patient-specific enhancer function in primary MLL-rearranged leukemia samples. Proteomic analysis further demonstrates that Menin associates with distinct transcriptional and elongation complexes in MLL::AF4 compared to NPM1c cells, supporting a context-dependent mechanism of action. Together, these findings establish that Menin is not a uniform transcriptional cofactor, but a context-dependent regulator of enhancer connectivity, and identifies enhancer-promoter architecture as a selective vulnerability in MLL-rearranged leukemia.

cancer biology↗

bioRxiv2022

Assessment of the Human Placental Microbiome in Early Pregnancy

Bacteria derived from the maternal circulation have been suggested to seed the human placenta during development leading to an intrinsic placental microbiome. This concept has become controversial as numerous studies suggest that the apparent placental microbiome is mostly, if not completely, comprised of contaminants. If the maternal circulation seeds the placenta then there should be an increase in abundance and diversity of detectable bacteria with onset of maternal perfusion of the placenta around 10 weeks gestational age; however, if only contaminants are present then there should be no significant evolution of the placental microbiome with increasing gestational age. This pilot study addresses whether bacterial abundance and diversity increases in human placenta and whether there is an associated shift in the immunophenotype of the decidual immune cell complement before and after initiation of placental perfusion. Human placental and decidual tissue from 5-19 weeks gestational age are assessed by quantitative 16S polymerase chain reaction (PCR), 16S gene sequencing, and immunological flow cytometry studies. A weak positive correlation between placental bacterial abundance and gestational age is identified but is not statistically significant. No significant changes in bacterial diversity are found with increasing gestational age. The proportion of decidual activated memory T helper cells increases with gestational age but no change was observed in other lymphocyte subsets. This pilot study does not strongly support bacterial colonization of the placenta after initiation of maternal perfusion; however, the minor trends towards increases in bacterial abundance and activated memory T helper cells may represent an early stage of this process. Additional investigations in larger cohorts are warranted.

physiology↗