Biology subjects

Muthukumar, R.

Publications and source records attributed to Muthukumar, R..

4 recordsLinked to original sources

bioRxiv2026

Reversible chromatin remodeling enables Prosopis cineraria survival under recurrent heat extremes.

Recurrent seasonal heat and drought raise fundamental questions about how long-lived desert plants sustain physiological function across temperature extremes. We have used seasonal profiling at six time points with multilayered omics studies (Hi-C, transcriptomic, histone marks, and DNA methylation) to understand how Prosopis cineraria, a native Arabian desert legume tree, responds to different temperatures and the underlying mechanisms. A clear pattern emerges during peak heat. chromatin boundaries are selectively weakened, and candidate topological domains merge, activating clusters of heat-protective genes that gain active promoter and enhancer marks (H3K4me3 and H3K27ac). In the cool season, immune and developmental gene regulation is coupled with flowering, consistent with a temporal risk-strategy that shifts reproduction away from lethal heat. At the same time, promoter CHH methylation near transposable elements, together with reduced active promoter and enhancer marks (H3K4me3/H3K27ac), points to a proactive developmental phase rather than just surviving the stress. Integrating physiological data, we connect chromatin activation to an SA-ABA reciprocal seasonal profile, MIZ1-associated hydrotropism, and Stay-Green-mediated delayed senescence through chlorophyll retention. With Landscape genomics and phylogenetics, we further identified a housekeeping PEPC with a high predicted melting temperature that could sustain a malate-derived carbon supply, buffering metabolism under heat. Together, these findings reveal that reversible epigenetic gating enables desert trees to survive and recover from extreme seasonal stress.

plant biology↗

bioRxiv2025

MLL3 and MLL4 sustain hematopoietic stem cell multipotency by opposing a B-cell default state

Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) are sustained by networks of transcription factors and epigenetic regulators that prime lineage-specific programs yet maintain multipotency. Two epigenetic regulators, MLL3 and MLL4, play important but opposing roles in maintaining this balance. MLL3 promotes HSC differentiation, whereas MLL4 opposes differentiation. These opposing functions are essential for both normal homeostasis and leukemia suppression, yet it is not clear how MLL3 and MLL4 regulate HSC and MPP gene expression to control HSC/MPP fate decisions. To resolve these mechanisms, we performed an extensive series of single cell genomic studies after conditionally deleting Mll3, Mll4 or both genes together. Mll3 deletion had only limited effects on HSC/MPP enhancer networks at steady state, whereas Mll4 deletion led to precocious activation of myeloid enhancers. Surprisingly, compound Mll3/4 deletion eliminated all myeloid, erythroid and megakaryocytic potential within the hematopoietic hierarchy and caused all progenitors to rapidly default to a B-cell-like identity. These changes were accompanied by widespread inactivation of HSC/MPP enhancers and superenhancers, and ectopic activation of B-cell superenhancers. Disabling MLL3/4 histone methyltransferase activity did not recapitulate the pervasive changes in cell identity that were observed when MLL3 and MLL4 were fully inactivated, indicating that MLL3 and MLL4 activate HSC/MPP enhancers independently from their enzymatic activities. Our findings show that HSC/MPP multipotency requires sustained tension between MLL3/4-dependent enhancers that maintain myeloid, erythroid and megakaryocyte potential, and MLL3/4-independent enhancers that prime B-cell identity. MLL3 and MLL4 therefore serve as critical linchpins of multilineage hematopoiesis. KEY POINTSO_LIMLL3 and MLL4 act redundantly in HSCs to sustain transcription factor and enhancer networks that support multipotency C_LIO_LISimultaneous loss of MLL3 and MLL4 drives hematopoietic progenitors into a uniform B-cell-like default state C_LI

cell biology↗

bioRxiv2025

SKIDA1 transiently sustains MLL::ENL-Expressing hematopoietic progenitors during neonatal stages and promotes B-lineage priming

Infant leukemias arise as B-cell acute lymphocytic (B-ALL) or acute myeloid leukemia (AML). The majority are driven by chromosomal rearrangements of the MLL/ KMT2A gene (MLLr) and arise in utero, implying a fetal cell of origin. Fetal and neonatal hematopoietic progenitors have unique transcriptomes and epigenomes, raising the question of whether MLL fusion proteins activate distinct target gene profiles during these early stages of life. Here, we use a transgenic mouse model of MLL::ENL-driven leukemia to identify Skida1 as a target gene that is more highly induced in fetal and neonatal progenitors than in adult progenitors. SKIDA1 is highly expressed in human MLLr leukemias and the protein associates with the Polycomb Repressive Complex 2 (PRC2). We show that Skida1 is dispensable for normal hematopoiesis, but it promotes B-cell priming and maintains MLL::ENL-expressing hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) during neonatal development. Conditional deletion of Skida1 has no effect on normal HSC function, yet it impairs B-cell production from neonatal MLL::ENL-expressing HSCs while leaving myeloid leukemogenesis unaffected. Temporally-restricted targets of MLL fusion proteins, such as SKIDA1, can therefore tune cell fates at different ages, potentially influencing the types MLLr leukemias that arise at different ages.

cancer biology↗

bioRxiv2025

Fetal context conveys heritable protection against MLL-rearranged leukemia that depends on MLL3

MLL rearrangements (MLLr) are the most common cause of congenital and infant leukemias. MLLr arise prior to birth and require few cooperating mutations for transformation, yet congenital leukemias are 10-fold less common than infant leukemias and >100-fold less common than childhood leukemias overall. This raises the question of whether mechanisms exist to suppress leukemic transformation during fetal life, thereby protecting the developing fetus from malignancy during a period of rapid hematopoietic progenitor expansion. Here, we use mouse models to show that fetal MLL::ENL exposure creates a heritable, leukemia-resistant state. MLL::ENL imposes a negative selective pressure on fetal hematopoietic progenitors. It leads to postnatal loss of self-renewal gene expression and enhanced myeloid differentiation that precludes transformation. These changes do not occur when MLL::ENL is induced shortly after birth, and transformation proceeds efficiently in this context. The fetal barrier to transformation is enforced by the histone methyltransferase MLL3. It can be overcome by cooperating mutations, such as NrasG12D, or through somatic or germline inactivation of MLL3. Heritable fetal protection against leukemic transformation may explain the low incidence of congenital leukemias in humans despite prenatal MLL rearrangement.

cancer biology↗