The University of Michigan Medical School
Human Genetics Department
Ann Arbor, MI, 48108
Email: siwase@umich.edu
Phone: +1-734-647-8832
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Selected Publications
Cell Mol Neurobiol​. 2025 Jul 7;45(1):62.
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We systematically investigate the consequences of the PHF21A c.1285G>A variant on mRNA splicing and DNA binding. Our results indicate that the variant significantly reduces the splicing efficiency of PHF21A isoforms while maintaining DNA binding capability. Thus, reduced dosage rather than impaired DNA binding likely contributes to the cognitive impairments seen in the individual with this variant.
Cell Rep​. 2025 Jun 24;44(6):115746.
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We identify an instructive role for H3K4me in controlling synapse function and a division of labor among the six KMT2 enzymes in regulating homeostatic synaptic scaling. Using RNAi screening, conditional genetics, small-molecule inhibitors, and transcriptional profiling, our data reveal that individual KMT2 enzymes have unique roles and operate in specific phases to control distinct facets of homeostatic scaling. Together, our results suggest that the expansion of this enzyme family in mammals is key to coupling fine-tuned gene expression changes to adaptive modifications of synaptic function.
Cell Rep​. 2025 Jan 15;44(1):115-213.
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We uncovered neuron-specific splicing events for 14 chromatin regulators, including H3K4 demethylase LSD1 and reader PHF21A. Alternative splicing of ubiquitously-expressed chromatin regulators, therefore, can exert neuron-specific function.
J Biol Chem​. 2024 Nov;300(11):107881.
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We report that neuronal PHF21A isoform expression precedes neuronal LSD1 expression during human neuron differentiation and mouse brain development. We used two Phf21a mouse models to show that Phf21a neuronal splicing prevents excess synapse formation that otherwise would occur when canonical PHF21A is expressed in neurons, suggesting that the role of the PHF21A microexon is to dampen LSD1-mediated H3K4 demethylation, thereby containing aberrant synaptogenesis.
FEBS J​. 2022 Apr;289(8):2301-2317.
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We examine how impaired germline gene repression by chromatin regulators may lead to impaired brain development & function in certain neurodevelopmental disorders (NDDs). We also discuss how to test hypotheses to determine the contribution of ectopic germline transcripts to chromatin-NDDs.
Genome Res. 2021 Jan 7;31(2):186-197.
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We found that loss of Kdm1a in mouse neurons lead to premature activation of neuronal activity-dependent enhancers & genes. A basic research step towards understanding the associated human KDM1A / LSD1 neurodevelopmental syndrome.
Cell Rep. 2020 Aug 11;32(6):108002.
August 10, 2020
We devised metabolic labeling of nascent RNAs and sequencing in the neural ensemble. Using this approach, we found a role of RAI1, Smith-Magenis Syndrome gene, in neuronal-activity dependent transcription and synaptic plasticity. Great collaboration with Dr. Michael Sutton lab at Michigan Neuroscience Institute.
Communications Biology 2020 Jun 1;3(1):278.
June 01, 2020
We found mutually suppressive roles of H3K4me writer KMT2A and eraser KDM5C. This work provides proof of the principle of modulating single methyl histone enzymes to ameliorate neurodevelopmental disorders. Great collaboration with Tronson Lab!
Front Mol Neurosci 11:104
April 04, 2018
Christina's first first-author research article. We describe a patient mutation in KDM5C which has altered gene regulatory function in neurons.
Neuroscience 370:170-180
May 29, 2017
Bobby's first first-author research paper published.
Cell Rep. 14(5):1000-9.
February 09, 2016
Characterization of Kdm5c-Knockout mice. These mice will be valuable for future therapeutic development of intellectual disability and autism spectrum disorders.
Nat Commun. ;6:6002. doi: 10.1038/ncomms7002.
January 22, 2015
The first paper from the lab! We developped a new RNA-seq method which allows us to profile full-length transcripts.
Nat Struct Mol Biol. 18(7):769-76. doi: 10.1038/nsmb.2062.
June 22, 2011
We found that ADD domain of ATRX, which is enriched with ATRX-syndrome mutations, is a reading module for heterochromatin histone methylation status, low H3K4me and hight H3K9me3.
Cell. 128(6):1077-88. Epub 2007 Feb 22.
February 22, 2007
We discovered the first family of enzymes which can remove H3K4me3. One of the family members, JARID1C/KDM5C was known to be mutated in X-linked intellectual disability. We linked hitone methylation dynamics and human cognitive development for the first time.
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