Biology subjects

Mallen, J.

Publications and source records attributed to Mallen, J..

4 recordsLinked to original sources

bioRxiv2024

The evolutionary ancient MEIS transcription factors actuate lineage-specific transcription to establish cardiac fate

Control of gene expression is commonly mediated by distinct combinations of transcription factors (TFs). This cooperative action allows multiple biological signals to be integrated at specific regulatory elements, resulting in highly specific gene expression patterns in space and time. It is unclear whether combinatorial binding is also necessary to bring together TFs with distinct biochemical functions, which collaborate to effectively recruit and activate RNA polymerase II. Using a cardiac differentiation model, we find that the largely ubiquitous, evolutionary ancient homeodomain proteins MEIS are essential for activating a cardiac-specific gene expression program. MEIS TFs act as actuators, fully activating transcriptional programs selected by lineage-restricted TFs to drive the dynamic progression of cardiac differentiation. Combinatorial binding of MEIS with lineage-enriched TFs, GATA and HOX, provides selectivity, guiding MEIS to function at cardiac-specific enhancers. In turn, MEIS TFs promote accumulation of the methyltransferase KMT2D to initiate lineage-specific enhancer commissioning. MEIS combinatorial binding dynamics, dictated by the changing dosage of its partners, drive cells into progressive stages of cardiac differentiation. Our results uncover tissue-specific transcriptional activation as the result of ubiquitous actuator TFs harnessing general transcriptional coactivators at tissue-specific enhancers, to which they are directed by binding with lineage- and domain-specific TFs.

developmental biology↗

bioRxiv2023

A pipeline to identify TF combinatorial binding uncovers TEAD1 as an antagonist of tissue-specific transcription factors in human organogenesis

Gene expression is largely controlled by transcription factors (TFs), which bind to enhancers in combination with other TFs in a mechanism known as combinatorial binding. While combinatorial binding is well established, a comprehensive view of tissue-specific TF combinations at active enhancers during human embryonic development is still lacking. Using a two-step pipeline to detect co-occurring TF motifs in developmental enhancers across 11 human embryonic tissues, we found that motifs recognized by ubiquitous TF families, including TEAD, TALE, ETS, and STAT, are enriched near tissue-specific sequence signatures in developmental enhancers across multiple tissues. In human heart enhancers, TEAD and GATA motifs frequently co-occur, and in the developing mouse heart TEAD1 and GATA4 co-occupy a set of genomic regions, which are also preferentially bound by CHD4, a component of the NuRD complex involved in transcriptional repression. Consistently, TEAD1 attenuates enhancer activation in vitro, with this repressive effect dependent on tissue-specific activators. Overall, our findings reveal universal patterns of TF connectivity within organ-specific transcriptional networks and highlight a broad, previously unrecognized role for TEAD in coordinating organ growth and differentiation across multiple tissues.

genomics↗

bioRxiv2023

A cell atlas of the human outflow tract of the heart and its adult derivatives

The outflow tract (OFT) of the heart carries blood away from the heart into the great arteries. During embryogenesis, the OFT divides to form the aorta and pulmonary trunk, creating the double circulation present in mammals. Defects in this area account for one-third of all congenital heart defect cases. Here, we present comprehensive transcriptomic data on the developing OFT at two distinct timepoints (embryonic and fetal) and its adult derivatives, the aortic valves, and use spatial transcriptomics to define the distribution of cell populations. We uncover that distinctive embryonic signatures persist in adult cells and can be used as labels to retrospectively attribute relationships between cells separated by a large time scale. Single-cell regulatory network inference identifies GATA6, a transcription factor linked to common arterial trunk and bicuspid aortic valve, as a key regulator of valve precursor cells. Its downstream network reveals candidate drivers of human cardiac defects and illuminates the molecular mechanisms of both normal and pathological valve development. Our findings define the cellular and molecular signatures of the human OFT and its distinct cell lineages, which is critical for understanding congenital heart defects and developing cardiac tissue for regenerative medicine.

developmental biology↗

bioRxiv2019

HOX paralogs selectively convert binding of ubiquitous transcription factors into tissue-specific patterns of enhancer activation

Gene expression programs determine cell fate in embryonic development and their dysregulation results in disease. Transcription factors (TFs) control gene expression by binding to enhancers, but how TFs select and activate their target enhancers is still unclear. HOX TFs share conserved homeodomains with highly similar sequence recognition properties, yet they impart the identity of different animal body parts. To understand how HOX TFs control their specific transcriptional programs in vivo, we compared HOXA2 and HOXA3 binding profiles in the mouse embryo. HOXA2 and HOXA3 directly cooperate with TALE TFs and selectively target different subsets of a broad TALE chromatin platform. Binding of HOX and tissue-specific TFs convert low affinity TALE binding into high confidence, tissue-specific binding events, which bear the mark of active enhancers. We propose that HOX paralogs, alone and in combination with tissue-specific TFs, generate tissue-specific transcriptional outputs by modulating the activity of TALE TFs at selected enhancers.

developmental biology↗