A National Cancer Institute-designated Comprehensive Cancer Center

Make an appointment: 800-826-HOPE
Singer-Sam, Judith, Ph.D. Laboratory Bookmark and Share

Laboratory of Judith Singer-Sam, Ph.D.

For a growing number of genes, only one of the two chromosomal copies (or alleles) is expressed, a phenomenon termed monoallelic expression. In some cases, there is random selection of the expressed allele; in others parental origin determines which allele is expressed, which is termed imprinting. Disorders with a genetic component in which either random monoallelic expression or imprinting may play a role include schizophrenia, multiple sclerosis, and diabetes.
 
Our goal is to understand the mechanism and extent of imprinting and monoallelic expression, and their possible relevance to inherited disorders, particularly those of the central nervous system. Towards this goal, we are studying a mouse locus corresponding to a human inherited mental retardation disorder known to involve imprinted genes, the Prader-Willi/Angelman Syndrome. We are also developing an assay that would make use of state-of-the-art microarray technology to probe for imprinting and monoallelic expression in the entire genome.
 

Judith Singer-Sam, Ph.D. Research

Monoallelic Expression in the Central Nervous System
Although most genes in a cell are expressed from both the maternal and paternal chromosome, there are exceptions. For example, in women, most X-linked genes are expressed from only one of the two X chromosomes, a phenomenon called X inactivation. In addition, there is a class of autosomal genes, termed imprinted genes, for which parental origin determines which allele is expressed. Finally, there are autosomal genes that appear at first glance to be bi-allelically expressed but actually show random monoallelic expression (sometimes termed allelic exclusion) at the single-cell level. These exceptions, examples of epigenetics, have proven to be of great interest for researchers because they shed light on gene regulation, chromatin structure, development, and the pattern of inheritance of certain genetic disorders.
 
My research program is focused on the potential role of allele-specific expression in development and function of the central nervous system (CNS). What is the evidence that genes likely to play a role in CNS function show such expression? Olfactory receptors, which are expressed in specialized cells of the CNS, show allelic exclusion, as does p120 catenin, which is involved in synapse formation. Intriguing recent work has shown that a number of factors involved in the immune response, including the genes for interleukin-2 and interleukin-4, also show allelic exclusion. Some of these genes are expressed in the CNS, and the possibility arises that other inflammation-sensitive genes in the CNS may show a similar pattern of expression.  Using gene expression profiling, we discovered that, Cdkn1a, coding for the cell cycle regulator p21Waf1/Cip1, is inflammation-sensitive in the CNS as well as other tissues.  While this gene is bi-allelically expressed, we expect to find additional immune response genes that do undergo monoallelic expression.
 
We have also developed an imprinting screen using expression microarrays. As a model system, we analyzed mice with imprinting defects in proximal chromosome 7; part of this region is analogous to human chromosome 15q11-q13, a locus associated with a number of behavioral and cognitive disorders including the well-studied Prader-Willi/Angelman Syndrome (PW/AS). Our analysis revealed the presence of two novel paternally expressed intergenic transcripts at the mouse PW/AS locus, in a region highly enriched in LINE-1 elements; the function of these transcripts is still unknown.  In separate work, we discovered, in collaboration with Dr. Chauncey Bowers (Department of Neurosciences) that the dense LINE-1 elements in this region are organized in a uniquely asymmetric way, perhaps related to imprinting at the locus.
 
Our current work involves the identification and characterization of genes that are subject to random monoallelic expression in the CNS. We have developed a microarray-based assay for genes that are both silenced and active at the same locus as evidenced by a dual DNA methylation pattern.  We further analyze candidate genes using SNP differences in cDNA of clonal neural stem cell lines derived from F1 hybrids of two different strains of mice. We have found a number of “hits” and are currently characterizing those that appear potentially most relevant to disorders of the CNS.
 

Singer-Sam, Judith, Ph.D. Laboratory

Laboratory of Judith Singer-Sam, Ph.D.

For a growing number of genes, only one of the two chromosomal copies (or alleles) is expressed, a phenomenon termed monoallelic expression. In some cases, there is random selection of the expressed allele; in others parental origin determines which allele is expressed, which is termed imprinting. Disorders with a genetic component in which either random monoallelic expression or imprinting may play a role include schizophrenia, multiple sclerosis, and diabetes.
 
Our goal is to understand the mechanism and extent of imprinting and monoallelic expression, and their possible relevance to inherited disorders, particularly those of the central nervous system. Towards this goal, we are studying a mouse locus corresponding to a human inherited mental retardation disorder known to involve imprinted genes, the Prader-Willi/Angelman Syndrome. We are also developing an assay that would make use of state-of-the-art microarray technology to probe for imprinting and monoallelic expression in the entire genome.
 

Research

Judith Singer-Sam, Ph.D. Research

Monoallelic Expression in the Central Nervous System
Although most genes in a cell are expressed from both the maternal and paternal chromosome, there are exceptions. For example, in women, most X-linked genes are expressed from only one of the two X chromosomes, a phenomenon called X inactivation. In addition, there is a class of autosomal genes, termed imprinted genes, for which parental origin determines which allele is expressed. Finally, there are autosomal genes that appear at first glance to be bi-allelically expressed but actually show random monoallelic expression (sometimes termed allelic exclusion) at the single-cell level. These exceptions, examples of epigenetics, have proven to be of great interest for researchers because they shed light on gene regulation, chromatin structure, development, and the pattern of inheritance of certain genetic disorders.
 
My research program is focused on the potential role of allele-specific expression in development and function of the central nervous system (CNS). What is the evidence that genes likely to play a role in CNS function show such expression? Olfactory receptors, which are expressed in specialized cells of the CNS, show allelic exclusion, as does p120 catenin, which is involved in synapse formation. Intriguing recent work has shown that a number of factors involved in the immune response, including the genes for interleukin-2 and interleukin-4, also show allelic exclusion. Some of these genes are expressed in the CNS, and the possibility arises that other inflammation-sensitive genes in the CNS may show a similar pattern of expression.  Using gene expression profiling, we discovered that, Cdkn1a, coding for the cell cycle regulator p21Waf1/Cip1, is inflammation-sensitive in the CNS as well as other tissues.  While this gene is bi-allelically expressed, we expect to find additional immune response genes that do undergo monoallelic expression.
 
We have also developed an imprinting screen using expression microarrays. As a model system, we analyzed mice with imprinting defects in proximal chromosome 7; part of this region is analogous to human chromosome 15q11-q13, a locus associated with a number of behavioral and cognitive disorders including the well-studied Prader-Willi/Angelman Syndrome (PW/AS). Our analysis revealed the presence of two novel paternally expressed intergenic transcripts at the mouse PW/AS locus, in a region highly enriched in LINE-1 elements; the function of these transcripts is still unknown.  In separate work, we discovered, in collaboration with Dr. Chauncey Bowers (Department of Neurosciences) that the dense LINE-1 elements in this region are organized in a uniquely asymmetric way, perhaps related to imprinting at the locus.
 
Our current work involves the identification and characterization of genes that are subject to random monoallelic expression in the CNS. We have developed a microarray-based assay for genes that are both silenced and active at the same locus as evidenced by a dual DNA methylation pattern.  We further analyze candidate genes using SNP differences in cDNA of clonal neural stem cell lines derived from F1 hybrids of two different strains of mice. We have found a number of “hits” and are currently characterizing those that appear potentially most relevant to disorders of the CNS.
 
Our Scientists

Our research laboratories are led by the best and brightest minds in scientific research.
 

Beckman Research Institute of City of Hope is internationally  recognized for its innovative biomedical research.
City of Hope is one of only 41 Comprehensive Cancer Centers in the country, the highest designation awarded by the National Cancer Institute to institutions that lead the way in cancer research, treatment, prevention and professional education.
Learn more about City of Hope's institutional distinctions, breakthrough innovations and collaborations.
Develop new therapies, diagnostics and preventions in the fight against cancer and other life-threatening diseases.
 
Support Our Research
By giving to City of Hope, you support breakthrough discoveries in laboratory research that translate into lifesaving treatments for patients with cancer and other serious diseases.
 
 
 
 


NEWS & UPDATES
  • To say that myelofibrosis patients need more treatment options would be an understatement. The severely low platelet counts, known as thrombocytopenia, that are one of the hallmark symptoms of the disease can lead to chronic fatigue and weakness that not only damage quality of life but, ultimately, shorten life...
  • Patients with metastatic colorectal cancer often stop responding to the primary drugs used against the disease, leaving them with few options and little hope. Determined to increase those options, doctors and researchers at City of Hope are conducting two clinical trials that could lead to new treatments for pe...
  • Investigators working at City of Hope are making many significant inroads against many forms of cancer. To do that, they have to take a variety of approaches. Molecular oncology researchers focus on abnormal cancer-associated activity in a cell’s nucleus. One especially prominent factor in many breast and ovari...
  • In light of the new breast cancer screening guidelines, which call for women to have mammograms every other year from age 50 to 74, it’s more important than ever for women to understand their individual risk. On Monday, the U.S. Preventive Services Task force released new breast cancer screening guideline...
  • Cancer patients need, and deserve, more than medical care. They and their families need high-quality supportive care – that is, care that addresses their physical, emotional and spiritual well-being. Health care professionals increasingly understand this, but starting such programs from scratch isn’t easy...
  • Each year, City of Hope patients given another chance at life gather to pose for a picture like this one. Going on its 39th year, the celebration of patients free of blood cancers thanks to bone marrow or stem cell transplants has grown such that a photographer has to scale a cherry picker just to […]
  • Cancer patients who are participating in early-stage clinical trials need extra emotional and physical support due to their additional stress and often unique symptoms. Now an effort by researchers at City of Hope to create a model for such support has received a $6.8 million grant from the National Cancer Inst...
  • The need for improvements in treating malignant brain tumors has never been greater. Survival for many patients with these tumors are sometimes measured in just months. One reason that therapeutic options are limited is that traditional surgery is deemed too risky for many brain tumors, especially for those in ...
  • “Honestly, there’s nothing special about my story,” protested Daniel Samson, as he bounced Layla, his 3 1/2-year-old daughter, on his lap and put on a video for her to watch. “I just want to tell it for my own sake, and share it with other men who may be going through this chaos.” Samson spoke […]
  • As far back as he can remember, Jonathan Yamzon, M.D., wanted to be a doctor. “I knew it from the get-go,” he said, matter-of-factly. “I always envisioned it as the ideal; the supreme thing one could do with one’s life.” The youngest of six children, Yamzon was barely a toddler when his family moved to [&...
  • There’s never a “good” time for cancer to strike. With testicular cancer, the timing can seem particularly unfair. This disease targets young adults in the prime of life; otherwise healthy people unaccustomed to any serious illness, let alone cancer. And suddenly … “I can only imagine what they must...
  • Sure, a healthy lifestyle can lower a person’s risk, but the impact of specific actions is harder to tease out. Diet, exercise, tobacco use, nutritional supplements, alcohol consumption … How important are each of these factors, individually? Does strict adherence to (or rejection of) one get you a pass o...
  • Health care decisions are tough. They’re even tougher when you – or loved ones – have to make them without a plan or a conversation. National Healthcare Decisions Day, on April 16,  is a nationwide initiative to demystify the health care decision-making process and encourage families to start talking. Ult...
  • The statistics, direct from the American Cancer Society, are sobering: Cancer death rates among African-American men are 27 percent higher than for white men. The death rate for African-American women is 11 percent higher compared to white women. Hispanics have higher rates of cervical, liver and stomach cancer...
  • “Lucky” is not usually a term used to describe someone diagnosed with cancer.  But that’s how 34-year-old Alex Camargo’s doctor described him when he was diagnosed with thyroid cancer — the disease is one of the most treatable cancers at all stages. That doctor was ultimately proved righ...