Research
We study how hematopoietic cells control ribosome biogenesis, from the machinery that sets its pace to the influence it has on normal and leukemic states.
How does a cell set the pace of its ribosome factory?
Every cell must decide how many ribosomes to build, and at what speed. This decision is made in the nucleolus, where RNA Polymerase I synthesizes ribosomal RNA. It is one of the least studied control knobs in the cell.
In any given cell, only a fraction of its hundreds of ribosomal DNA repeats are active, and the activity of Pol I on these templates controls rRNA transcription. We built custom genomes to map this repetitive DNA and found that many of the transcription factors that guide blood development and drive leukemia, including CEBPA, RUNX, SPI1, IRF8, and MYC, bind ribosomal DNA directly. Manipulation of several of these factors immediately impairs Pol I activity and reduces rRNA transcription.
What we are testing now
We aim to precisely map out the mechanisms underlying cell-type-specific control of ribosome numbers.
rDNA chromatin dynamics
Defining how rDNA repeats are opened and closed during cell state transitionsTranscription factors
Mapping how lineage factors tune rRNA transcriptionPol I in vivo
Tracking Pol I in living animals with reporter miceLive imaging
Watching single Pol I molecules transcribe in living cellsHundreds of rDNA repeats per cell. Every cell makes its own decisions about how to transcribe them.
Why do different blood cells need different numbers of ribosomes?
A stem cell, a progenitor, and a mature blood cell each have distinct numbers of ribosomes. We do not quite understand why, or to what end.
Across the hematopoietic tree, rRNA transcription varies about ten-fold, rising as stem cells commit to a lineage and falling as they mature to their final forms. Unexpectedly, these rates do not perfectly track with how much protein a cell makes or how fast it divides. This suggests that ribosome number is a regulated property in its own right, one that may help decide the fate and capacities of the cell.
What we are testing now
We aim to determine how alterations in ribosome numbers affect the ability of blood cells to maintain their homeostatic functions, and how subtle changes can affect cell states and identities.
Ribosomes and cell fate
Testing whether ribosome number steers hematopoietic stemness and lineage choiceSelective translation
Asking which mRNAs need a threshold of ribosomes to be translatedImmune activation
Tracing how rRNA transcription ramps up in T cell activation and memoryRibosome lifespan
Measuring how long an individual ribosome lives, and whether ribosome turnover instructs cell behaviorMillions of ribosomes per cell. Each cell needs a precise number to achieve its goals.
How does leukemia hijack the ribosome factory, and can we selectively repress it?
In acute leukemia, the ribosome factory runs in overdrive. This is an Achilles' heel we hope to target.
Leukemia cells have long been recognized by their enlarged nucleoli, evidence of abundant ribosome production. We showed directly that leukemic cells transcribe more rRNA and contain more ribosomes than their normal counterparts. Leukemia depends on keeping this factory in overdrive, and not only to fuel cell division. High rates of ribosome production help sustain the leukemic state itself, creating a dependence we can exploit.
What we are testing now
We aim to define the oncogenic mechanisms that rely on high ribosome numbers, and to develop new ways of crippling ribosome production that selectively target leukemic cells while sparing normal ones.
Nucleolar kinetics
Exploring how the enlarged leukemic nucleolus is organized and driven differently from normal cellsThe MYC link
Dissecting how the master oncogene dictates rRNA transcriptionSelective inhibition
Dialing down leukemic rRNA transcription to force arrest and differentiationSynergistic targeting
Understanding whether nucleolar targeting can pair with existing therapies to reach the clinicFor over a century, leukemia cells have been marked by enlarged nucleoli. We aim to target them.
Our approach
The nucleolus, its hundreds of near-identical DNA repeats, and the rRNAs transcribed from them, have been challenging to study with standard tools. We have built new tools to help advance research in this field, working across the bench and the computer.